Research ArticleSynthesis Characterization and Antihypertensive Evaluation ofSome Novel 2288-Tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-b1015840]dipyranDerivatives

Pankaj Dwivedi1 Kuldipsinh P Barot2 Shailesh Jain2 and Manjunath D Ghate2

1Department of Pharmaceutical Chemistry Krupanidhi College of Pharmacy Bangalore 35 India2Department of Pharmaceutical Chemistry Institute of Pharmacy Nirma University Ahmedabad Gujarat 382481 India

Correspondence should be addressed to Manjunath D Ghate manjunathghatenirmauniacin

Received 24 June 2014 Accepted 3 January 2015

Academic Editor Georgia Melagraki

Copyright copy 2015 Pankaj Dwivedi et alThis is an open access article distributed under the Creative CommonsAttribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A series of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-b1015840]dipyran derivatives7andashe and 8andashe were synthesized from resorcinol All the synthesized compounds were characterized by FTIR mass spectra and1H NMR These compounds were evaluated for antihypertensive activity using Wister Albino Rat model Direct antihypertensiveactivity was performed using the instrument BIOPAC System MP-36 Santa Barbara California for recording blood pressureresponse Among the title compounds compounds 7b 7c and 7d showed potent antihypertensive activity and other compoundswere also found to exert low and moderate antihypertensive activity The relaxant potency in rat aorta and trachea was used forbiological characterization of the benzopyrans Structure-activity relationships study was investigated around position-4 of thebenzopyran nucleus

1 Introduction

Potassium specific channels are assorted group of ion chan-nels and play a fundamental role in the modulation of cellexcitability [1 2] Potassium channel classifications and theirpharmacological activities have been reviewed extensively[3] The term ldquopotassium channel openers (KCOs)rdquo wasintroduced to designate a group of novel synthetic moleculeswhich are specified by cromakalim It led to a new directionin the pharmacology of ion channels by reporting thatcromakalim evoked smooth muscle relaxant effects by theopening of K+ channels in cell membranes [4] It has initiatedmajor research efforts in the search for other such moleculesand in the determination of the specific channel(s) involved[5] KCO properties are demonstrated in a diverse rangeof synthetic chemical structures and endogenous substances[6]

Cromakalim evoked a contractile response in rabbit aortabathed in a Ca2+ free solution which is related to the effects

on intracellular Ca2+ stores [7] These findings support thoseobtained from vascular smooth muscle where contractileresponses to noradrenaline depend on intracellular calciumstores which are attenuated by cromakalim [8] In contrastthe effect of cromakalim on rat pulmonary artery did notappear to involve an action on Ca2+ release from internalstores [9] A variety of compounds having a benzopyransuch as levocromakalim bimakalim and Y-27152 generallyexhibit potent antihypertensive activity Benzodipyrans havestructural and chemical similarity with the cromakalim [10]The ATP-sensitive potassium channel (KATP) openers (egchromakalim) were originally developed for the treatmentof hypertension due to their potent peripheral vasodilatingproperties [11] To find more potent vasodilators variousbenzopyran derivatives modified at position-4 were synthe-sized and structure-activity relationship was examined byevaluation of the extent and duration of the increase incoronary blood flow in anesthetized dogs [12] Compoundshaving a 1 6-dihydro-6-oxopyridazin-3-yl amino group at

Hindawi Publishing CorporationAdvances in ChemistryVolume 2015 Article ID 850974 8 pageshttpdxdoiorg1011552015850974

2 Advances in Chemistry

O

NC

H

H

OH

N

I

O

O

N

NH

O

V

O

Ominus

N+ N

N

O

VI

NH2

H2N

N+minus

O3SN

SH

NHS

HO

IV

CH3

NH

NC

II

N

NH

N

CH3

CH3

CH3

CH3

NH

NSCl

OO

III

CH3

Figure 1 First generation potassium channel openers (KCOs) as antihypertensive agents

position-4 in addition to the two methoxymethyl groupsat position-2 were found to be more potent and have animproved duration of action [13]

Myocardial preconditioning as KCOs is of great inter-est as myocardial protecting agents [14] The first gener-ation (KATP) openers IndashVI (Figure 1) are potent periph-eral vasodilators but the use of these compounds for thetreatment of acute myocardial ischemia is limited due tothe possibility of hemodynamic alterations upon systemicadministration which can result in under perfusion of thearea that is already at risk [15] It was presumed that clinicalutility of these agents for the treatment of hypertension isdue to their peripheral vasodilating properties as they arewidely known to open potassium channels in several tissuetypes But relevant studies have shown that KATP openershave direct cardioprotective properties independent of theirvasodilator effectTherefore tissue selective KATP openers areclearly required to explore the potential of these agents [16]

2 Experimental

21 General All the reagents were purchased from Sigma-Aldrich Chemicals (Bangalore India) and were used withoutfurther purification All solvents were distilled and driedusing dry sieves as the usual manner TLC analysis wascarried out on aluminum foil precoated with silica gel 60F254 (Sigma-Aldrich Bangalore dealer) Melting points weredetermined on a Thomas micro-hot stage apparatus and areuncorrected FTIR spectra were determined as KBr soliddiscs on a Shimadzu model 470 spectrophotometer 1HNMR spectra were recorded using a Jeol Eclipse 400MHzspectrometer using CDCl

3as NMR solvent and are reported

in ppm down field from the residual CDCl3 1H NMR

spectrum exhibited different signals at different ppm whichwere assigned to the different types of protons The syntheticroute leading to the title compounds is summarized inScheme 1

22 Synthesis

221 24-Diacetyl Resorcinol (2) Dry resorcinol 1 (10 g909mmol) was added to a mixture of zinc chloride (2467 g1818mmol) in dried acetic anhydride (189mL 1818mmol)in a round bottom flask quickly with stirring The reactionmixture was slowly heated on wire gauze and kept at 145ndash150∘C for 15min The resulting viscous reaction mixturewas allowed to cool at room temperature and ice coldaqueous hydrochloride solutionwas added to it with constantstirring An orange-red crystalline compound separated outwhich was purified by column chromatography to obtainwhite color solid compound Yield 7058mp 175ndash177∘CIR (KBr) ] (cmminus1) 34143 30798 29261 16586 1588612567 1HNMR (CDCl

3 120575 ppm) 1293 (s Ar 2H) 819 (s

1H) 639 (s 1H) 262 (s 6H) MS (EIMS FAB mz) 1954(M + 1)

222 2288-Tetramethyl-2378-tetrahydro-4H6H-benzo-[12-b54-1198871015840]-dipyran-46-dione (3) 24-Diacetyl resorcinol 2(10 g 515mmol) was mixed with piperidine (0875 g103mmol) and acetone (30mL) in toluene in a roundbottom flask which was fixed with Dean Stark apparatusTheresulting reaction mixture was slowly heated at 120ndash125∘Cfor 24 hr After completion of reaction the reaction mixturewas distilled off to remove the solvents It was quenchedwith ice cold water and extracted with chloroform Organiclayer was separated and dried over sodium sulfate and solvent

Advances in Chemistry 3

HO OH

1

HO OH

O O

2

O O

O O

3

O O

OH OH

O O

5

O O

O O

6

O O

OR

OH

O O

R

OH

R

HO

(CH3CO)2O ZnCl2

Δ140ndash145∘C

30min

LAH dry ether

Δ40ndash45∘C 1h

CH3COCH3toluene

Δ120ndash125∘C24h

HCl-water

Δ60ndash65∘C 15h

m-CPBA DCM

R-NH2

R-NH2

C2H5OH

C2H5OH

R = benzyl 34-dichlorobenzyl N-methyl piperazine diethyl dibenzyl and so forth

8 (andashe)

7 (andashe)

Δ60ndash65∘C 1ndash15h

Δ70ndash75∘C 1ndash15h

4

NH

CH3H3C

stir 0ndash5∘C 6-7h

Scheme 1 Synthesis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives7andashe and 8andashe from resorcinol for antihypertensive activity

was evaporated off The compound was purified by columnchromatography over silica gel to get a white color solidproduct Yield 5185mp 184ndash186∘C IR (KBr) ] (cmminus1)29734 29297 17031 16009 12342 1H NMR (CDCl

3 120575

ppm) 846 (s 1H) 638 (s 1H) 269 (s 4H) 145 (s 12H)MS (EIMS FABmz) 2751 (M + 1)

223 2288-Tetramethyl-2378-tetrahydro-4H6H-benzo-[12-b54-1198871015840]dipyran-46-dihydroxy (4) To a solution contain-ing 500mg (0013mol) of lithium aluminum hydride (LAH)in 25mL ether the corresponding chromanone 3 (137 g0005mole) in 30mL of ether was added drop wise withstirring in a round bottom flask The resulting reactionmixture was heated to reflux for an hour allowed to cooland then filtered Acetone (20mL) was added to the resultingfiltrate to decompose the excess of lithium aluminumhydrideand the reaction was monitored by TLC Yield 6543 mp183ndash185∘C IR (KBr) ] (cmminus1) 32817 29722 23618 163011254 1H NMR (CDCl

3 120575 ppm) 833 (d 3H) 646 (s 2H)

292 (s 2H) 152 (s 4H) MS (EIMS FAB mz) 2797 (M +1)

224 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran(5) Compound 4 was refluxed with 6M HCl (10mL) for10min Then 50mL water was added to it and the reactionmixture was further refluxed for 10 h allowed to cool solventwas evaporated off and aqueous phase was extracted withmethylene chloride Organic layer was dried over sodium sul-fate concentrated and purified by column chromatographyover silica gel to get a white color solid product Yield 8319mp 195ndash197∘C IR (KBr) ] (cmminus1) 30427 29775 15627 121271H NMR (CDCl

3 120575 ppm) 661 (s 1H) 627 (s 2H) 625 (d

1H J = 99Hz) 547 (d 1H J = 99Hz) 142 (s 12H) MS(EIMS FABmz) 2435 (M + 1)

225 2288-Tetramethyl-2H8H-benzo-[12-b54-1198871015840]dipyranOxide (6) Compound 5 (100mg 0413mmol) was dissolvedin dichloromethane m-Chloroperbenzoic acid (m-CPBA)(213mg 1239mmol) was added to resulting reaction mix-ture It was allowed to stir at 0∘C for 1 h Solvent wasevaporated at low temperature and excess of m-CPBA wasdecomposed by NaHCO

3solution The aqueous solution

was extracted using dichloromethane and organic layer was

4 Advances in Chemistry

separated It was concentrated and purified by column chro-matography over silica gel to get a white color solid productYield 3709 mp 186ndash188∘C IR (KBr) ] (cmminus1) 3074329345 15535 12433 10434 1H NMR (CDCl

3 120575ppm) 754

(d 1H J = 96Hz) 632 (d 1H J = 78Hz) 627 (s 1H) 246(s 3H) MS (EIMS FABmz) 2751 (M + 1)

226 2288-Tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran Derivatives(7andashe) and 2288-Tetramethyl-2378-tetrahydro-46-diam-ino-37-dihydroxy-benzo-[12-b54-1198871015840]dipyran Derivatives (8andashe) Compound 6 (100mg 0364mmol) was dissolved in30mL ethanol in a 100mL round bottom flask Benzylamine(078mL 729mmol)was added to the above reactionmixtureand was allowed to reflux at 80∘C for 3 h and reaction wasmonitored by TLC After completion of reaction it wasdistilled off to remove solvent from the reaction mixtureThen it was quenched with ice cold water and extracted withdichloromethane Organic layer was distilled off to get crudeproduct Further purification was accomplished by columnchromatography Mobile phase ethyl acetate hexane = 64

23 Antihypertensive Activity

231 Toxicity Studies to Fix Up LD50 Toxicity studies were

carried out according to the OECD guidelines numbers420 and 421 in order to fix up the dose to carry outthe antihypertensive activity [17 18] Wister Albino Ratsweighing 200ndash250 g were chosen and oral route is selectedfor the drug administration Six groups of animals eachcontaining three animals were initially selected as per theguidelines numbers 420 and 421 Given dose of 70mgkgbody weight was monitored in the animal for the toxicsymptoms as well as mortality [19] The animals showedhigh toxicity symptoms such as increased intestinal motilitydiarrhoea tail erection and irritation to nose and all theanimals were dead after 30 h Hence we decreased the doseto 50mgkg body weight and administered to the next groupof animals monitored for toxic symptoms and mortality Inthis dose animalswere safe but showed fewer toxic symptomsand only few were died Toxicity symptoms were diarrhoeatail erection and irritation to the nose Once again wedecreased the dose and it was fixed to a dose of 20mgkgbody weight to the next set of animals and observed for thetoxic symptoms and mortality All the animals were safe andno toxic symptoms were seen at this specific dose Henceit was concluded that 20mgkg body weight dose was safeand recommended dose for further antihypertensive activity[20]

232 Direct Antihypertensive Activity Direct antihyperten-sive activity was carried out using the instrument BIOPACSystem MP-36 Santa Barbara California for recording theblood pressure response [21] The instrument was calibratedbefore carrying out the experiment and process was thor-oughly practiced and understood including handling andsurgically cannulating artery for monitoring blood pressureand a vein for drug administration [22 23]

233 Preparation of Model Male albino rats weighing 200ndash250 g were used for the antihypertensive activity Rats wereanesthetized using urethane hydrochloride (125 gkg) Ratswere prepared by shaving the neck and inguinal region usinganimal hair clippers Jugular vein was surgically cannulatedfor the drug administration Left carotid artery was isolatedand exposed by dissection for blood pressure recording usingPE-50 tubing [24] By means of a three-way plastic stop cockand a stainless steel needle at the end of the PE tubingarterial cannula and venous cannulawere attached to a blood-pressure transducer and syringe respectively [25 26] Fluidwas filled in the both cannulae with heparinised saline beforecannulation Arterial cannula was connected via the BSLpressure transducer (SS13L) to the BIOPAC Systems IncCriterion for antihypertensive activity was the reduction ofsystolic arterial pressure by about 10ndash20mmHg [27]

234 Experimental Procedure Adrenaline (50 120583gkg iv)was administered intravenously for the sympathetic systemactivation to induce hypertension [28 29] Venous cannulawas flushed with 02mL of normal saline and allowed toreturn to preinjection level Test compound 20mgkg solu-tion was injected intravenously and allowed to equilibrationin the system Adrenaline (50 120583gkg iv) was repeated asdescribed previously Blood-pressure response was observedand recorded to each procedure [30ndash32] Antihypertensiveactivity of the benzodipyran derivatives 7andashe and 8andashc wassummarized in Table 1

3 Result and Discussion

31 Chemistry 4 6-Diacetyl resorcinol 2 was synthesizedusing a mixture of zinc chloride in dried acetic anhydridefrom dry resorcinol 1 by constant stirring It was kept athigh temperature for 30min and was purified throughcolumn chromatography [33 34] Compound 3 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]di-pyran-46-dione) was synthesized from 46-diacetyl resor-cinol using acetone and piperidine in a solution in a DeanStark apparatus using toluene as solvent The reactionmixture was slowly heated at 120ndash125∘C for 24 h to get thecompound 3 [35 36] Compound 4 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]dipyran-46-di-hydroxy) was synthesized using lithium aluminum hydride(LAH) in ether the corresponding chromanone in ether andboth these solutions were added drop wise with stirring Theresulting reaction mixture was heated to reflux for 1 h [37]This reaction mixture was taken as such for the synthesisof 2288-tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran 5by adding 6M HCl and allowed to reflux for 15 h Aftercompletion of the reaction solvent was evaporated and theremaining aqueous phase was extracted with methylenechloride [38 39] 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran oxide 6 was synthesized from compound5 by dissolving in dichloromethane and required quantityof m-chloroperbenzoic acid (m-CPBA) was added to it Theresulting reaction mixture was allowed to stir at 0ndash5∘C for6-7 h [40] Different benzodipyran derivatives 7andashe and 8andashe

Advances in Chemistry 5

Table 1 Antihypertensive activity of the benzodipyran derivatives 7andashe and 8andashc

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

7a

SBP 1012(plusmn0693)

1478(plusmn1308)

1406(plusmn1121)

1414(plusmn2040)

Minimal activityDBP 579

(plusmn0769)792(plusmn0861)

832(plusmn1240)

739(plusmn1167)

MABP 775(plusmn0480)

1439(plusmn1202)

1072(plusmn1387)

1093(plusmn0894)

HR 1965(plusmn3201)

2919(plusmn3158)

2481(plusmn3118)

2602(plusmn3201)

7b

SBP 1064(plusmn0482)

1606(plusmn1198)

1246(plusmn1389)

1260(plusmn1406)

AntihypertensiveDBP 478

(plusmn0927)751(plusmn3054)

530(plusmn0107)

593(plusmn1541)

MABP 7297(plusmn0890)

1221(plusmn1883)

8344(plusmn0488)

1092(plusmn0931)

HR 2999(plusmn3106)

3260(plusmn5431)

3210(plusmn0557)

3024(plusmn3658)

7c

SBP 1057(plusmn1203)

1482(plusmn1055)

1271(plusmn1031)

1324(plusmn2049)

AntihypertensiveDBP 631

(plusmn1202)865(plusmn1218)

621(plusmn3983)

842(plusmn1160)

MABP 681(plusmn0399)

1091(plusmn0963)

1198(plusmn1991)

1013(plusmn0896)

HR 2788(plusmn2697)

3021(plusmn2616)

2987(plusmn2065)

2964(plusmn3120)

7d

SBP 1208(plusmn1061)

1627(plusmn1211)

1436(plusmn0892)

1217(plusmn0231)

AntihypertensiveDBP 642

(plusmn0381)868(plusmn0665)

846(plusmn0820)

711(plusmn1858)

MABP 982(plusmn0485)

1207(plusmn1390)

1117(plusmn1057)

992(plusmn1524)

HR 2095(plusmn1161)

2672(plusmn1108)

2489(plusmn2868)

2668(plusmn2830)

7e

SBP 1089(plusmn0519)

1354(plusmn1328)

1608(plusmn0940)

1670(plusmn3027)

Moderately activeDBP 610

(plusmn1291)871(plusmn1966)

682(plusmn1332)

913(plusmn1857)

MABP 889(plusmn1135)

1021(plusmn1503)

1062(plusmn1887)

1193(plusmn0197)

HR 2322(plusmn2097)

2410(plusmn3088)

2092(plusmn3210)

2161(plusmn2118)

8a

SBP 1288(plusmn362)

1827(plusmn263)

1688(plusmn085)

1980(plusmn343)

Minimal activityDBP 7089

(plusmn233)1084(plusmn202)

1343(plusmn095)

1431(plusmn393)

MABP 1037(plusmn328)

1393(plusmn1532)

1499(plusmn1152)

1639(plusmn0852)

HR 2864(plusmn5128)

3046(plusmn3210)

3386(plusmn3308)

3419(plusmn1409)

8b

SBP 1068(plusmn2367)

1786(plusmn1349)

1793(plusmn2101)

1893(plusmn0239)

No activityDBP 840

(plusmn2105)1262(plusmn0968)

1287(plusmn1151)

1486(plusmn1059)

MABP 1129(plusmn2250)

1467(plusmn2152)

1823(plusmn1788)

1956(plusmn1272)

HR 3063(plusmn3977)

3318(plusmn3300)

346(plusmn2312)

3618(plusmn2008)

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

2 Advances in Chemistry

O

NC

H

H

OH

N

I

O

O

N

NH

O

V

O

Ominus

N+ N

N

O

VI

NH2

H2N

N+minus

O3SN

SH

NHS

HO

IV

CH3

NH

NC

II

N

NH

N

CH3

CH3

CH3

CH3

NH

NSCl

OO

III

CH3

Figure 1 First generation potassium channel openers (KCOs) as antihypertensive agents

position-4 in addition to the two methoxymethyl groupsat position-2 were found to be more potent and have animproved duration of action [13]

Myocardial preconditioning as KCOs is of great inter-est as myocardial protecting agents [14] The first gener-ation (KATP) openers IndashVI (Figure 1) are potent periph-eral vasodilators but the use of these compounds for thetreatment of acute myocardial ischemia is limited due tothe possibility of hemodynamic alterations upon systemicadministration which can result in under perfusion of thearea that is already at risk [15] It was presumed that clinicalutility of these agents for the treatment of hypertension isdue to their peripheral vasodilating properties as they arewidely known to open potassium channels in several tissuetypes But relevant studies have shown that KATP openershave direct cardioprotective properties independent of theirvasodilator effectTherefore tissue selective KATP openers areclearly required to explore the potential of these agents [16]

2 Experimental

21 General All the reagents were purchased from Sigma-Aldrich Chemicals (Bangalore India) and were used withoutfurther purification All solvents were distilled and driedusing dry sieves as the usual manner TLC analysis wascarried out on aluminum foil precoated with silica gel 60F254 (Sigma-Aldrich Bangalore dealer) Melting points weredetermined on a Thomas micro-hot stage apparatus and areuncorrected FTIR spectra were determined as KBr soliddiscs on a Shimadzu model 470 spectrophotometer 1HNMR spectra were recorded using a Jeol Eclipse 400MHzspectrometer using CDCl

3as NMR solvent and are reported

in ppm down field from the residual CDCl3 1H NMR

spectrum exhibited different signals at different ppm whichwere assigned to the different types of protons The syntheticroute leading to the title compounds is summarized inScheme 1

22 Synthesis

221 24-Diacetyl Resorcinol (2) Dry resorcinol 1 (10 g909mmol) was added to a mixture of zinc chloride (2467 g1818mmol) in dried acetic anhydride (189mL 1818mmol)in a round bottom flask quickly with stirring The reactionmixture was slowly heated on wire gauze and kept at 145ndash150∘C for 15min The resulting viscous reaction mixturewas allowed to cool at room temperature and ice coldaqueous hydrochloride solutionwas added to it with constantstirring An orange-red crystalline compound separated outwhich was purified by column chromatography to obtainwhite color solid compound Yield 7058mp 175ndash177∘CIR (KBr) ] (cmminus1) 34143 30798 29261 16586 1588612567 1HNMR (CDCl

3 120575 ppm) 1293 (s Ar 2H) 819 (s

1H) 639 (s 1H) 262 (s 6H) MS (EIMS FAB mz) 1954(M + 1)

222 2288-Tetramethyl-2378-tetrahydro-4H6H-benzo-[12-b54-1198871015840]-dipyran-46-dione (3) 24-Diacetyl resorcinol 2(10 g 515mmol) was mixed with piperidine (0875 g103mmol) and acetone (30mL) in toluene in a roundbottom flask which was fixed with Dean Stark apparatusTheresulting reaction mixture was slowly heated at 120ndash125∘Cfor 24 hr After completion of reaction the reaction mixturewas distilled off to remove the solvents It was quenchedwith ice cold water and extracted with chloroform Organiclayer was separated and dried over sodium sulfate and solvent

Advances in Chemistry 3

HO OH

1

HO OH

O O

2

O O

O O

3

O O

OH OH

O O

5

O O

O O

6

O O

OR

OH

O O

R

OH

R

HO

(CH3CO)2O ZnCl2

Δ140ndash145∘C

30min

LAH dry ether

Δ40ndash45∘C 1h

CH3COCH3toluene

Δ120ndash125∘C24h

HCl-water

Δ60ndash65∘C 15h

m-CPBA DCM

R-NH2

R-NH2

C2H5OH

C2H5OH

R = benzyl 34-dichlorobenzyl N-methyl piperazine diethyl dibenzyl and so forth

8 (andashe)

7 (andashe)

Δ60ndash65∘C 1ndash15h

Δ70ndash75∘C 1ndash15h

4

NH

CH3H3C

stir 0ndash5∘C 6-7h

Scheme 1 Synthesis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives7andashe and 8andashe from resorcinol for antihypertensive activity

was evaporated off The compound was purified by columnchromatography over silica gel to get a white color solidproduct Yield 5185mp 184ndash186∘C IR (KBr) ] (cmminus1)29734 29297 17031 16009 12342 1H NMR (CDCl

3 120575

ppm) 846 (s 1H) 638 (s 1H) 269 (s 4H) 145 (s 12H)MS (EIMS FABmz) 2751 (M + 1)

223 2288-Tetramethyl-2378-tetrahydro-4H6H-benzo-[12-b54-1198871015840]dipyran-46-dihydroxy (4) To a solution contain-ing 500mg (0013mol) of lithium aluminum hydride (LAH)in 25mL ether the corresponding chromanone 3 (137 g0005mole) in 30mL of ether was added drop wise withstirring in a round bottom flask The resulting reactionmixture was heated to reflux for an hour allowed to cooland then filtered Acetone (20mL) was added to the resultingfiltrate to decompose the excess of lithium aluminumhydrideand the reaction was monitored by TLC Yield 6543 mp183ndash185∘C IR (KBr) ] (cmminus1) 32817 29722 23618 163011254 1H NMR (CDCl

3 120575 ppm) 833 (d 3H) 646 (s 2H)

292 (s 2H) 152 (s 4H) MS (EIMS FAB mz) 2797 (M +1)

224 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran(5) Compound 4 was refluxed with 6M HCl (10mL) for10min Then 50mL water was added to it and the reactionmixture was further refluxed for 10 h allowed to cool solventwas evaporated off and aqueous phase was extracted withmethylene chloride Organic layer was dried over sodium sul-fate concentrated and purified by column chromatographyover silica gel to get a white color solid product Yield 8319mp 195ndash197∘C IR (KBr) ] (cmminus1) 30427 29775 15627 121271H NMR (CDCl

3 120575 ppm) 661 (s 1H) 627 (s 2H) 625 (d

1H J = 99Hz) 547 (d 1H J = 99Hz) 142 (s 12H) MS(EIMS FABmz) 2435 (M + 1)

225 2288-Tetramethyl-2H8H-benzo-[12-b54-1198871015840]dipyranOxide (6) Compound 5 (100mg 0413mmol) was dissolvedin dichloromethane m-Chloroperbenzoic acid (m-CPBA)(213mg 1239mmol) was added to resulting reaction mix-ture It was allowed to stir at 0∘C for 1 h Solvent wasevaporated at low temperature and excess of m-CPBA wasdecomposed by NaHCO

3solution The aqueous solution

was extracted using dichloromethane and organic layer was

4 Advances in Chemistry

separated It was concentrated and purified by column chro-matography over silica gel to get a white color solid productYield 3709 mp 186ndash188∘C IR (KBr) ] (cmminus1) 3074329345 15535 12433 10434 1H NMR (CDCl

3 120575ppm) 754

(d 1H J = 96Hz) 632 (d 1H J = 78Hz) 627 (s 1H) 246(s 3H) MS (EIMS FABmz) 2751 (M + 1)

226 2288-Tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran Derivatives(7andashe) and 2288-Tetramethyl-2378-tetrahydro-46-diam-ino-37-dihydroxy-benzo-[12-b54-1198871015840]dipyran Derivatives (8andashe) Compound 6 (100mg 0364mmol) was dissolved in30mL ethanol in a 100mL round bottom flask Benzylamine(078mL 729mmol)was added to the above reactionmixtureand was allowed to reflux at 80∘C for 3 h and reaction wasmonitored by TLC After completion of reaction it wasdistilled off to remove solvent from the reaction mixtureThen it was quenched with ice cold water and extracted withdichloromethane Organic layer was distilled off to get crudeproduct Further purification was accomplished by columnchromatography Mobile phase ethyl acetate hexane = 64

23 Antihypertensive Activity

231 Toxicity Studies to Fix Up LD50 Toxicity studies were

carried out according to the OECD guidelines numbers420 and 421 in order to fix up the dose to carry outthe antihypertensive activity [17 18] Wister Albino Ratsweighing 200ndash250 g were chosen and oral route is selectedfor the drug administration Six groups of animals eachcontaining three animals were initially selected as per theguidelines numbers 420 and 421 Given dose of 70mgkgbody weight was monitored in the animal for the toxicsymptoms as well as mortality [19] The animals showedhigh toxicity symptoms such as increased intestinal motilitydiarrhoea tail erection and irritation to nose and all theanimals were dead after 30 h Hence we decreased the doseto 50mgkg body weight and administered to the next groupof animals monitored for toxic symptoms and mortality Inthis dose animalswere safe but showed fewer toxic symptomsand only few were died Toxicity symptoms were diarrhoeatail erection and irritation to the nose Once again wedecreased the dose and it was fixed to a dose of 20mgkgbody weight to the next set of animals and observed for thetoxic symptoms and mortality All the animals were safe andno toxic symptoms were seen at this specific dose Henceit was concluded that 20mgkg body weight dose was safeand recommended dose for further antihypertensive activity[20]

232 Direct Antihypertensive Activity Direct antihyperten-sive activity was carried out using the instrument BIOPACSystem MP-36 Santa Barbara California for recording theblood pressure response [21] The instrument was calibratedbefore carrying out the experiment and process was thor-oughly practiced and understood including handling andsurgically cannulating artery for monitoring blood pressureand a vein for drug administration [22 23]

233 Preparation of Model Male albino rats weighing 200ndash250 g were used for the antihypertensive activity Rats wereanesthetized using urethane hydrochloride (125 gkg) Ratswere prepared by shaving the neck and inguinal region usinganimal hair clippers Jugular vein was surgically cannulatedfor the drug administration Left carotid artery was isolatedand exposed by dissection for blood pressure recording usingPE-50 tubing [24] By means of a three-way plastic stop cockand a stainless steel needle at the end of the PE tubingarterial cannula and venous cannulawere attached to a blood-pressure transducer and syringe respectively [25 26] Fluidwas filled in the both cannulae with heparinised saline beforecannulation Arterial cannula was connected via the BSLpressure transducer (SS13L) to the BIOPAC Systems IncCriterion for antihypertensive activity was the reduction ofsystolic arterial pressure by about 10ndash20mmHg [27]

234 Experimental Procedure Adrenaline (50 120583gkg iv)was administered intravenously for the sympathetic systemactivation to induce hypertension [28 29] Venous cannulawas flushed with 02mL of normal saline and allowed toreturn to preinjection level Test compound 20mgkg solu-tion was injected intravenously and allowed to equilibrationin the system Adrenaline (50 120583gkg iv) was repeated asdescribed previously Blood-pressure response was observedand recorded to each procedure [30ndash32] Antihypertensiveactivity of the benzodipyran derivatives 7andashe and 8andashc wassummarized in Table 1

3 Result and Discussion

31 Chemistry 4 6-Diacetyl resorcinol 2 was synthesizedusing a mixture of zinc chloride in dried acetic anhydridefrom dry resorcinol 1 by constant stirring It was kept athigh temperature for 30min and was purified throughcolumn chromatography [33 34] Compound 3 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]di-pyran-46-dione) was synthesized from 46-diacetyl resor-cinol using acetone and piperidine in a solution in a DeanStark apparatus using toluene as solvent The reactionmixture was slowly heated at 120ndash125∘C for 24 h to get thecompound 3 [35 36] Compound 4 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]dipyran-46-di-hydroxy) was synthesized using lithium aluminum hydride(LAH) in ether the corresponding chromanone in ether andboth these solutions were added drop wise with stirring Theresulting reaction mixture was heated to reflux for 1 h [37]This reaction mixture was taken as such for the synthesisof 2288-tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran 5by adding 6M HCl and allowed to reflux for 15 h Aftercompletion of the reaction solvent was evaporated and theremaining aqueous phase was extracted with methylenechloride [38 39] 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran oxide 6 was synthesized from compound5 by dissolving in dichloromethane and required quantityof m-chloroperbenzoic acid (m-CPBA) was added to it Theresulting reaction mixture was allowed to stir at 0ndash5∘C for6-7 h [40] Different benzodipyran derivatives 7andashe and 8andashe

Advances in Chemistry 5

Table 1 Antihypertensive activity of the benzodipyran derivatives 7andashe and 8andashc

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

7a

SBP 1012(plusmn0693)

1478(plusmn1308)

1406(plusmn1121)

1414(plusmn2040)

Minimal activityDBP 579

(plusmn0769)792(plusmn0861)

832(plusmn1240)

739(plusmn1167)

MABP 775(plusmn0480)

1439(plusmn1202)

1072(plusmn1387)

1093(plusmn0894)

HR 1965(plusmn3201)

2919(plusmn3158)

2481(plusmn3118)

2602(plusmn3201)

7b

SBP 1064(plusmn0482)

1606(plusmn1198)

1246(plusmn1389)

1260(plusmn1406)

AntihypertensiveDBP 478

(plusmn0927)751(plusmn3054)

530(plusmn0107)

593(plusmn1541)

MABP 7297(plusmn0890)

1221(plusmn1883)

8344(plusmn0488)

1092(plusmn0931)

HR 2999(plusmn3106)

3260(plusmn5431)

3210(plusmn0557)

3024(plusmn3658)

7c

SBP 1057(plusmn1203)

1482(plusmn1055)

1271(plusmn1031)

1324(plusmn2049)

AntihypertensiveDBP 631

(plusmn1202)865(plusmn1218)

621(plusmn3983)

842(plusmn1160)

MABP 681(plusmn0399)

1091(plusmn0963)

1198(plusmn1991)

1013(plusmn0896)

HR 2788(plusmn2697)

3021(plusmn2616)

2987(plusmn2065)

2964(plusmn3120)

7d

SBP 1208(plusmn1061)

1627(plusmn1211)

1436(plusmn0892)

1217(plusmn0231)

AntihypertensiveDBP 642

(plusmn0381)868(plusmn0665)

846(plusmn0820)

711(plusmn1858)

MABP 982(plusmn0485)

1207(plusmn1390)

1117(plusmn1057)

992(plusmn1524)

HR 2095(plusmn1161)

2672(plusmn1108)

2489(plusmn2868)

2668(plusmn2830)

7e

SBP 1089(plusmn0519)

1354(plusmn1328)

1608(plusmn0940)

1670(plusmn3027)

Moderately activeDBP 610

(plusmn1291)871(plusmn1966)

682(plusmn1332)

913(plusmn1857)

MABP 889(plusmn1135)

1021(plusmn1503)

1062(plusmn1887)

1193(plusmn0197)

HR 2322(plusmn2097)

2410(plusmn3088)

2092(plusmn3210)

2161(plusmn2118)

8a

SBP 1288(plusmn362)

1827(plusmn263)

1688(plusmn085)

1980(plusmn343)

Minimal activityDBP 7089

(plusmn233)1084(plusmn202)

1343(plusmn095)

1431(plusmn393)

MABP 1037(plusmn328)

1393(plusmn1532)

1499(plusmn1152)

1639(plusmn0852)

HR 2864(plusmn5128)

3046(plusmn3210)

3386(plusmn3308)

3419(plusmn1409)

8b

SBP 1068(plusmn2367)

1786(plusmn1349)

1793(plusmn2101)

1893(plusmn0239)

No activityDBP 840

(plusmn2105)1262(plusmn0968)

1287(plusmn1151)

1486(plusmn1059)

MABP 1129(plusmn2250)

1467(plusmn2152)

1823(plusmn1788)

1956(plusmn1272)

HR 3063(plusmn3977)

3318(plusmn3300)

346(plusmn2312)

3618(plusmn2008)

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Advances in Chemistry 3

HO OH

1

HO OH

O O

2

O O

O O

3

O O

OH OH

O O

5

O O

O O

6

O O

OR

OH

O O

R

OH

R

HO

(CH3CO)2O ZnCl2

Δ140ndash145∘C

30min

LAH dry ether

Δ40ndash45∘C 1h

CH3COCH3toluene

Δ120ndash125∘C24h

HCl-water

Δ60ndash65∘C 15h

m-CPBA DCM

R-NH2

R-NH2

C2H5OH

C2H5OH

R = benzyl 34-dichlorobenzyl N-methyl piperazine diethyl dibenzyl and so forth

8 (andashe)

7 (andashe)

Δ60ndash65∘C 1ndash15h

Δ70ndash75∘C 1ndash15h

4

NH

CH3H3C

stir 0ndash5∘C 6-7h

Scheme 1 Synthesis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives7andashe and 8andashe from resorcinol for antihypertensive activity

was evaporated off The compound was purified by columnchromatography over silica gel to get a white color solidproduct Yield 5185mp 184ndash186∘C IR (KBr) ] (cmminus1)29734 29297 17031 16009 12342 1H NMR (CDCl

3 120575

ppm) 846 (s 1H) 638 (s 1H) 269 (s 4H) 145 (s 12H)MS (EIMS FABmz) 2751 (M + 1)

223 2288-Tetramethyl-2378-tetrahydro-4H6H-benzo-[12-b54-1198871015840]dipyran-46-dihydroxy (4) To a solution contain-ing 500mg (0013mol) of lithium aluminum hydride (LAH)in 25mL ether the corresponding chromanone 3 (137 g0005mole) in 30mL of ether was added drop wise withstirring in a round bottom flask The resulting reactionmixture was heated to reflux for an hour allowed to cooland then filtered Acetone (20mL) was added to the resultingfiltrate to decompose the excess of lithium aluminumhydrideand the reaction was monitored by TLC Yield 6543 mp183ndash185∘C IR (KBr) ] (cmminus1) 32817 29722 23618 163011254 1H NMR (CDCl

3 120575 ppm) 833 (d 3H) 646 (s 2H)

292 (s 2H) 152 (s 4H) MS (EIMS FAB mz) 2797 (M +1)

224 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran(5) Compound 4 was refluxed with 6M HCl (10mL) for10min Then 50mL water was added to it and the reactionmixture was further refluxed for 10 h allowed to cool solventwas evaporated off and aqueous phase was extracted withmethylene chloride Organic layer was dried over sodium sul-fate concentrated and purified by column chromatographyover silica gel to get a white color solid product Yield 8319mp 195ndash197∘C IR (KBr) ] (cmminus1) 30427 29775 15627 121271H NMR (CDCl

3 120575 ppm) 661 (s 1H) 627 (s 2H) 625 (d

1H J = 99Hz) 547 (d 1H J = 99Hz) 142 (s 12H) MS(EIMS FABmz) 2435 (M + 1)

225 2288-Tetramethyl-2H8H-benzo-[12-b54-1198871015840]dipyranOxide (6) Compound 5 (100mg 0413mmol) was dissolvedin dichloromethane m-Chloroperbenzoic acid (m-CPBA)(213mg 1239mmol) was added to resulting reaction mix-ture It was allowed to stir at 0∘C for 1 h Solvent wasevaporated at low temperature and excess of m-CPBA wasdecomposed by NaHCO

3solution The aqueous solution

was extracted using dichloromethane and organic layer was

4 Advances in Chemistry

separated It was concentrated and purified by column chro-matography over silica gel to get a white color solid productYield 3709 mp 186ndash188∘C IR (KBr) ] (cmminus1) 3074329345 15535 12433 10434 1H NMR (CDCl

3 120575ppm) 754

(d 1H J = 96Hz) 632 (d 1H J = 78Hz) 627 (s 1H) 246(s 3H) MS (EIMS FABmz) 2751 (M + 1)

226 2288-Tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran Derivatives(7andashe) and 2288-Tetramethyl-2378-tetrahydro-46-diam-ino-37-dihydroxy-benzo-[12-b54-1198871015840]dipyran Derivatives (8andashe) Compound 6 (100mg 0364mmol) was dissolved in30mL ethanol in a 100mL round bottom flask Benzylamine(078mL 729mmol)was added to the above reactionmixtureand was allowed to reflux at 80∘C for 3 h and reaction wasmonitored by TLC After completion of reaction it wasdistilled off to remove solvent from the reaction mixtureThen it was quenched with ice cold water and extracted withdichloromethane Organic layer was distilled off to get crudeproduct Further purification was accomplished by columnchromatography Mobile phase ethyl acetate hexane = 64

23 Antihypertensive Activity

231 Toxicity Studies to Fix Up LD50 Toxicity studies were

carried out according to the OECD guidelines numbers420 and 421 in order to fix up the dose to carry outthe antihypertensive activity [17 18] Wister Albino Ratsweighing 200ndash250 g were chosen and oral route is selectedfor the drug administration Six groups of animals eachcontaining three animals were initially selected as per theguidelines numbers 420 and 421 Given dose of 70mgkgbody weight was monitored in the animal for the toxicsymptoms as well as mortality [19] The animals showedhigh toxicity symptoms such as increased intestinal motilitydiarrhoea tail erection and irritation to nose and all theanimals were dead after 30 h Hence we decreased the doseto 50mgkg body weight and administered to the next groupof animals monitored for toxic symptoms and mortality Inthis dose animalswere safe but showed fewer toxic symptomsand only few were died Toxicity symptoms were diarrhoeatail erection and irritation to the nose Once again wedecreased the dose and it was fixed to a dose of 20mgkgbody weight to the next set of animals and observed for thetoxic symptoms and mortality All the animals were safe andno toxic symptoms were seen at this specific dose Henceit was concluded that 20mgkg body weight dose was safeand recommended dose for further antihypertensive activity[20]

232 Direct Antihypertensive Activity Direct antihyperten-sive activity was carried out using the instrument BIOPACSystem MP-36 Santa Barbara California for recording theblood pressure response [21] The instrument was calibratedbefore carrying out the experiment and process was thor-oughly practiced and understood including handling andsurgically cannulating artery for monitoring blood pressureand a vein for drug administration [22 23]

233 Preparation of Model Male albino rats weighing 200ndash250 g were used for the antihypertensive activity Rats wereanesthetized using urethane hydrochloride (125 gkg) Ratswere prepared by shaving the neck and inguinal region usinganimal hair clippers Jugular vein was surgically cannulatedfor the drug administration Left carotid artery was isolatedand exposed by dissection for blood pressure recording usingPE-50 tubing [24] By means of a three-way plastic stop cockand a stainless steel needle at the end of the PE tubingarterial cannula and venous cannulawere attached to a blood-pressure transducer and syringe respectively [25 26] Fluidwas filled in the both cannulae with heparinised saline beforecannulation Arterial cannula was connected via the BSLpressure transducer (SS13L) to the BIOPAC Systems IncCriterion for antihypertensive activity was the reduction ofsystolic arterial pressure by about 10ndash20mmHg [27]

234 Experimental Procedure Adrenaline (50 120583gkg iv)was administered intravenously for the sympathetic systemactivation to induce hypertension [28 29] Venous cannulawas flushed with 02mL of normal saline and allowed toreturn to preinjection level Test compound 20mgkg solu-tion was injected intravenously and allowed to equilibrationin the system Adrenaline (50 120583gkg iv) was repeated asdescribed previously Blood-pressure response was observedand recorded to each procedure [30ndash32] Antihypertensiveactivity of the benzodipyran derivatives 7andashe and 8andashc wassummarized in Table 1

3 Result and Discussion

31 Chemistry 4 6-Diacetyl resorcinol 2 was synthesizedusing a mixture of zinc chloride in dried acetic anhydridefrom dry resorcinol 1 by constant stirring It was kept athigh temperature for 30min and was purified throughcolumn chromatography [33 34] Compound 3 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]di-pyran-46-dione) was synthesized from 46-diacetyl resor-cinol using acetone and piperidine in a solution in a DeanStark apparatus using toluene as solvent The reactionmixture was slowly heated at 120ndash125∘C for 24 h to get thecompound 3 [35 36] Compound 4 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]dipyran-46-di-hydroxy) was synthesized using lithium aluminum hydride(LAH) in ether the corresponding chromanone in ether andboth these solutions were added drop wise with stirring Theresulting reaction mixture was heated to reflux for 1 h [37]This reaction mixture was taken as such for the synthesisof 2288-tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran 5by adding 6M HCl and allowed to reflux for 15 h Aftercompletion of the reaction solvent was evaporated and theremaining aqueous phase was extracted with methylenechloride [38 39] 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran oxide 6 was synthesized from compound5 by dissolving in dichloromethane and required quantityof m-chloroperbenzoic acid (m-CPBA) was added to it Theresulting reaction mixture was allowed to stir at 0ndash5∘C for6-7 h [40] Different benzodipyran derivatives 7andashe and 8andashe

Advances in Chemistry 5

Table 1 Antihypertensive activity of the benzodipyran derivatives 7andashe and 8andashc

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

7a

SBP 1012(plusmn0693)

1478(plusmn1308)

1406(plusmn1121)

1414(plusmn2040)

Minimal activityDBP 579

(plusmn0769)792(plusmn0861)

832(plusmn1240)

739(plusmn1167)

MABP 775(plusmn0480)

1439(plusmn1202)

1072(plusmn1387)

1093(plusmn0894)

HR 1965(plusmn3201)

2919(plusmn3158)

2481(plusmn3118)

2602(plusmn3201)

7b

SBP 1064(plusmn0482)

1606(plusmn1198)

1246(plusmn1389)

1260(plusmn1406)

AntihypertensiveDBP 478

(plusmn0927)751(plusmn3054)

530(plusmn0107)

593(plusmn1541)

MABP 7297(plusmn0890)

1221(plusmn1883)

8344(plusmn0488)

1092(plusmn0931)

HR 2999(plusmn3106)

3260(plusmn5431)

3210(plusmn0557)

3024(plusmn3658)

7c

SBP 1057(plusmn1203)

1482(plusmn1055)

1271(plusmn1031)

1324(plusmn2049)

AntihypertensiveDBP 631

(plusmn1202)865(plusmn1218)

621(plusmn3983)

842(plusmn1160)

MABP 681(plusmn0399)

1091(plusmn0963)

1198(plusmn1991)

1013(plusmn0896)

HR 2788(plusmn2697)

3021(plusmn2616)

2987(plusmn2065)

2964(plusmn3120)

7d

SBP 1208(plusmn1061)

1627(plusmn1211)

1436(plusmn0892)

1217(plusmn0231)

AntihypertensiveDBP 642

(plusmn0381)868(plusmn0665)

846(plusmn0820)

711(plusmn1858)

MABP 982(plusmn0485)

1207(plusmn1390)

1117(plusmn1057)

992(plusmn1524)

HR 2095(plusmn1161)

2672(plusmn1108)

2489(plusmn2868)

2668(plusmn2830)

7e

SBP 1089(plusmn0519)

1354(plusmn1328)

1608(plusmn0940)

1670(plusmn3027)

Moderately activeDBP 610

(plusmn1291)871(plusmn1966)

682(plusmn1332)

913(plusmn1857)

MABP 889(plusmn1135)

1021(plusmn1503)

1062(plusmn1887)

1193(plusmn0197)

HR 2322(plusmn2097)

2410(plusmn3088)

2092(plusmn3210)

2161(plusmn2118)

8a

SBP 1288(plusmn362)

1827(plusmn263)

1688(plusmn085)

1980(plusmn343)

Minimal activityDBP 7089

(plusmn233)1084(plusmn202)

1343(plusmn095)

1431(plusmn393)

MABP 1037(plusmn328)

1393(plusmn1532)

1499(plusmn1152)

1639(plusmn0852)

HR 2864(plusmn5128)

3046(plusmn3210)

3386(plusmn3308)

3419(plusmn1409)

8b

SBP 1068(plusmn2367)

1786(plusmn1349)

1793(plusmn2101)

1893(plusmn0239)

No activityDBP 840

(plusmn2105)1262(plusmn0968)

1287(plusmn1151)

1486(plusmn1059)

MABP 1129(plusmn2250)

1467(plusmn2152)

1823(plusmn1788)

1956(plusmn1272)

HR 3063(plusmn3977)

3318(plusmn3300)

346(plusmn2312)

3618(plusmn2008)

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

4 Advances in Chemistry

separated It was concentrated and purified by column chro-matography over silica gel to get a white color solid productYield 3709 mp 186ndash188∘C IR (KBr) ] (cmminus1) 3074329345 15535 12433 10434 1H NMR (CDCl

3 120575ppm) 754

(d 1H J = 96Hz) 632 (d 1H J = 78Hz) 627 (s 1H) 246(s 3H) MS (EIMS FABmz) 2751 (M + 1)

226 2288-Tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran Derivatives(7andashe) and 2288-Tetramethyl-2378-tetrahydro-46-diam-ino-37-dihydroxy-benzo-[12-b54-1198871015840]dipyran Derivatives (8andashe) Compound 6 (100mg 0364mmol) was dissolved in30mL ethanol in a 100mL round bottom flask Benzylamine(078mL 729mmol)was added to the above reactionmixtureand was allowed to reflux at 80∘C for 3 h and reaction wasmonitored by TLC After completion of reaction it wasdistilled off to remove solvent from the reaction mixtureThen it was quenched with ice cold water and extracted withdichloromethane Organic layer was distilled off to get crudeproduct Further purification was accomplished by columnchromatography Mobile phase ethyl acetate hexane = 64

23 Antihypertensive Activity

231 Toxicity Studies to Fix Up LD50 Toxicity studies were

carried out according to the OECD guidelines numbers420 and 421 in order to fix up the dose to carry outthe antihypertensive activity [17 18] Wister Albino Ratsweighing 200ndash250 g were chosen and oral route is selectedfor the drug administration Six groups of animals eachcontaining three animals were initially selected as per theguidelines numbers 420 and 421 Given dose of 70mgkgbody weight was monitored in the animal for the toxicsymptoms as well as mortality [19] The animals showedhigh toxicity symptoms such as increased intestinal motilitydiarrhoea tail erection and irritation to nose and all theanimals were dead after 30 h Hence we decreased the doseto 50mgkg body weight and administered to the next groupof animals monitored for toxic symptoms and mortality Inthis dose animalswere safe but showed fewer toxic symptomsand only few were died Toxicity symptoms were diarrhoeatail erection and irritation to the nose Once again wedecreased the dose and it was fixed to a dose of 20mgkgbody weight to the next set of animals and observed for thetoxic symptoms and mortality All the animals were safe andno toxic symptoms were seen at this specific dose Henceit was concluded that 20mgkg body weight dose was safeand recommended dose for further antihypertensive activity[20]

232 Direct Antihypertensive Activity Direct antihyperten-sive activity was carried out using the instrument BIOPACSystem MP-36 Santa Barbara California for recording theblood pressure response [21] The instrument was calibratedbefore carrying out the experiment and process was thor-oughly practiced and understood including handling andsurgically cannulating artery for monitoring blood pressureand a vein for drug administration [22 23]

233 Preparation of Model Male albino rats weighing 200ndash250 g were used for the antihypertensive activity Rats wereanesthetized using urethane hydrochloride (125 gkg) Ratswere prepared by shaving the neck and inguinal region usinganimal hair clippers Jugular vein was surgically cannulatedfor the drug administration Left carotid artery was isolatedand exposed by dissection for blood pressure recording usingPE-50 tubing [24] By means of a three-way plastic stop cockand a stainless steel needle at the end of the PE tubingarterial cannula and venous cannulawere attached to a blood-pressure transducer and syringe respectively [25 26] Fluidwas filled in the both cannulae with heparinised saline beforecannulation Arterial cannula was connected via the BSLpressure transducer (SS13L) to the BIOPAC Systems IncCriterion for antihypertensive activity was the reduction ofsystolic arterial pressure by about 10ndash20mmHg [27]

234 Experimental Procedure Adrenaline (50 120583gkg iv)was administered intravenously for the sympathetic systemactivation to induce hypertension [28 29] Venous cannulawas flushed with 02mL of normal saline and allowed toreturn to preinjection level Test compound 20mgkg solu-tion was injected intravenously and allowed to equilibrationin the system Adrenaline (50 120583gkg iv) was repeated asdescribed previously Blood-pressure response was observedand recorded to each procedure [30ndash32] Antihypertensiveactivity of the benzodipyran derivatives 7andashe and 8andashc wassummarized in Table 1

3 Result and Discussion

31 Chemistry 4 6-Diacetyl resorcinol 2 was synthesizedusing a mixture of zinc chloride in dried acetic anhydridefrom dry resorcinol 1 by constant stirring It was kept athigh temperature for 30min and was purified throughcolumn chromatography [33 34] Compound 3 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]di-pyran-46-dione) was synthesized from 46-diacetyl resor-cinol using acetone and piperidine in a solution in a DeanStark apparatus using toluene as solvent The reactionmixture was slowly heated at 120ndash125∘C for 24 h to get thecompound 3 [35 36] Compound 4 (2288-tetramethyl-2378-tetrahydro-4H6H-benzo[12-b54-1198871015840]dipyran-46-di-hydroxy) was synthesized using lithium aluminum hydride(LAH) in ether the corresponding chromanone in ether andboth these solutions were added drop wise with stirring Theresulting reaction mixture was heated to reflux for 1 h [37]This reaction mixture was taken as such for the synthesisof 2288-tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran 5by adding 6M HCl and allowed to reflux for 15 h Aftercompletion of the reaction solvent was evaporated and theremaining aqueous phase was extracted with methylenechloride [38 39] 2288-Tetramethyl-2H8H-benzo[12-b54-1198871015840]dipyran oxide 6 was synthesized from compound5 by dissolving in dichloromethane and required quantityof m-chloroperbenzoic acid (m-CPBA) was added to it Theresulting reaction mixture was allowed to stir at 0ndash5∘C for6-7 h [40] Different benzodipyran derivatives 7andashe and 8andashe

Advances in Chemistry 5

Table 1 Antihypertensive activity of the benzodipyran derivatives 7andashe and 8andashc

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

7a

SBP 1012(plusmn0693)

1478(plusmn1308)

1406(plusmn1121)

1414(plusmn2040)

Minimal activityDBP 579

(plusmn0769)792(plusmn0861)

832(plusmn1240)

739(plusmn1167)

MABP 775(plusmn0480)

1439(plusmn1202)

1072(plusmn1387)

1093(plusmn0894)

HR 1965(plusmn3201)

2919(plusmn3158)

2481(plusmn3118)

2602(plusmn3201)

7b

SBP 1064(plusmn0482)

1606(plusmn1198)

1246(plusmn1389)

1260(plusmn1406)

AntihypertensiveDBP 478

(plusmn0927)751(plusmn3054)

530(plusmn0107)

593(plusmn1541)

MABP 7297(plusmn0890)

1221(plusmn1883)

8344(plusmn0488)

1092(plusmn0931)

HR 2999(plusmn3106)

3260(plusmn5431)

3210(plusmn0557)

3024(plusmn3658)

7c

SBP 1057(plusmn1203)

1482(plusmn1055)

1271(plusmn1031)

1324(plusmn2049)

AntihypertensiveDBP 631

(plusmn1202)865(plusmn1218)

621(plusmn3983)

842(plusmn1160)

MABP 681(plusmn0399)

1091(plusmn0963)

1198(plusmn1991)

1013(plusmn0896)

HR 2788(plusmn2697)

3021(plusmn2616)

2987(plusmn2065)

2964(plusmn3120)

7d

SBP 1208(plusmn1061)

1627(plusmn1211)

1436(plusmn0892)

1217(plusmn0231)

AntihypertensiveDBP 642

(plusmn0381)868(plusmn0665)

846(plusmn0820)

711(plusmn1858)

MABP 982(plusmn0485)

1207(plusmn1390)

1117(plusmn1057)

992(plusmn1524)

HR 2095(plusmn1161)

2672(plusmn1108)

2489(plusmn2868)

2668(plusmn2830)

7e

SBP 1089(plusmn0519)

1354(plusmn1328)

1608(plusmn0940)

1670(plusmn3027)

Moderately activeDBP 610

(plusmn1291)871(plusmn1966)

682(plusmn1332)

913(plusmn1857)

MABP 889(plusmn1135)

1021(plusmn1503)

1062(plusmn1887)

1193(plusmn0197)

HR 2322(plusmn2097)

2410(plusmn3088)

2092(plusmn3210)

2161(plusmn2118)

8a

SBP 1288(plusmn362)

1827(plusmn263)

1688(plusmn085)

1980(plusmn343)

Minimal activityDBP 7089

(plusmn233)1084(plusmn202)

1343(plusmn095)

1431(plusmn393)

MABP 1037(plusmn328)

1393(plusmn1532)

1499(plusmn1152)

1639(plusmn0852)

HR 2864(plusmn5128)

3046(plusmn3210)

3386(plusmn3308)

3419(plusmn1409)

8b

SBP 1068(plusmn2367)

1786(plusmn1349)

1793(plusmn2101)

1893(plusmn0239)

No activityDBP 840

(plusmn2105)1262(plusmn0968)

1287(plusmn1151)

1486(plusmn1059)

MABP 1129(plusmn2250)

1467(plusmn2152)

1823(plusmn1788)

1956(plusmn1272)

HR 3063(plusmn3977)

3318(plusmn3300)

346(plusmn2312)

3618(plusmn2008)

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Advances in Chemistry 5

Table 1 Antihypertensive activity of the benzodipyran derivatives 7andashe and 8andashc

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

7a

SBP 1012(plusmn0693)

1478(plusmn1308)

1406(plusmn1121)

1414(plusmn2040)

Minimal activityDBP 579

(plusmn0769)792(plusmn0861)

832(plusmn1240)

739(plusmn1167)

MABP 775(plusmn0480)

1439(plusmn1202)

1072(plusmn1387)

1093(plusmn0894)

HR 1965(plusmn3201)

2919(plusmn3158)

2481(plusmn3118)

2602(plusmn3201)

7b

SBP 1064(plusmn0482)

1606(plusmn1198)

1246(plusmn1389)

1260(plusmn1406)

AntihypertensiveDBP 478

(plusmn0927)751(plusmn3054)

530(plusmn0107)

593(plusmn1541)

MABP 7297(plusmn0890)

1221(plusmn1883)

8344(plusmn0488)

1092(plusmn0931)

HR 2999(plusmn3106)

3260(plusmn5431)

3210(plusmn0557)

3024(plusmn3658)

7c

SBP 1057(plusmn1203)

1482(plusmn1055)

1271(plusmn1031)

1324(plusmn2049)

AntihypertensiveDBP 631

(plusmn1202)865(plusmn1218)

621(plusmn3983)

842(plusmn1160)

MABP 681(plusmn0399)

1091(plusmn0963)

1198(plusmn1991)

1013(plusmn0896)

HR 2788(plusmn2697)

3021(plusmn2616)

2987(plusmn2065)

2964(plusmn3120)

7d

SBP 1208(plusmn1061)

1627(plusmn1211)

1436(plusmn0892)

1217(plusmn0231)

AntihypertensiveDBP 642

(plusmn0381)868(plusmn0665)

846(plusmn0820)

711(plusmn1858)

MABP 982(plusmn0485)

1207(plusmn1390)

1117(plusmn1057)

992(plusmn1524)

HR 2095(plusmn1161)

2672(plusmn1108)

2489(plusmn2868)

2668(plusmn2830)

7e

SBP 1089(plusmn0519)

1354(plusmn1328)

1608(plusmn0940)

1670(plusmn3027)

Moderately activeDBP 610

(plusmn1291)871(plusmn1966)

682(plusmn1332)

913(plusmn1857)

MABP 889(plusmn1135)

1021(plusmn1503)

1062(plusmn1887)

1193(plusmn0197)

HR 2322(plusmn2097)

2410(plusmn3088)

2092(plusmn3210)

2161(plusmn2118)

8a

SBP 1288(plusmn362)

1827(plusmn263)

1688(plusmn085)

1980(plusmn343)

Minimal activityDBP 7089

(plusmn233)1084(plusmn202)

1343(plusmn095)

1431(plusmn393)

MABP 1037(plusmn328)

1393(plusmn1532)

1499(plusmn1152)

1639(plusmn0852)

HR 2864(plusmn5128)

3046(plusmn3210)

3386(plusmn3308)

3419(plusmn1409)

8b

SBP 1068(plusmn2367)

1786(plusmn1349)

1793(plusmn2101)

1893(plusmn0239)

No activityDBP 840

(plusmn2105)1262(plusmn0968)

1287(plusmn1151)

1486(plusmn1059)

MABP 1129(plusmn2250)

1467(plusmn2152)

1823(plusmn1788)

1956(plusmn1272)

HR 3063(plusmn3977)

3318(plusmn3300)

346(plusmn2312)

3618(plusmn2008)

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

6 Advances in Chemistry

Table 1 Continued

Comp code Parameter Baseline Withadrenaline

With testalone

With test +adrenaline Inference

8c

SBP 8982(plusmn1363)

1211(plusmn2015)

1433(plusmn138)

1475(plusmn1843)

Minimal activityDBP 671

(plusmn0379)895(plusmn0895)

1028(plusmn3516)

1233(plusmn2331)

MABP 880(plusmn3837)

1355(plusmn1293)

1428(plusmn2870)

1502(plusmn0922)

HR 2698(plusmn3897)

3021(plusmn4430)

3485(plusmn3772)

3569(plusmn1573)

SBP systolic blood pressure DBP diastolic blood pressure MABP mean arterial blood pressure and HR heart rate Values are expressed in mean plusmn SEMNumber of readings 03

Table 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-11988754-1198871015840]dipyran derivatives 7andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

7a NH2

C27H23O4N 31 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

3825

7b NHH3C N C21H30O4N2 3333178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

3740

7cCl

Cl NH2

C23H25Cl2O4N 2733955 (OndashH str) 29279 (Ali CndashH str)12566 (CndashO str) 16551 (C=C str)

10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

4511

7d NH

C28H29O4N 3332664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

4440

7e NH C20H29O4N 42

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

3482

Table 3 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-benzo[12-11988754-1198871015840] dipyran 8andashe

Comp code R Molecular formula 119877119891 FTIR (cmminus1) 1H NMR (ppm) Mass (M + 1)

8a NH2

C30H36O4N2 28 33527 (OndashH str) 29342 (Ali CndashH str)11388 (CndashN str) 1615 (C=C str)

120575716 (m 12H)120575215 (s 4H)120575130 (s 12H)

4891

8b NHH3C N C26 H42 O4N4 2733178 (OndashH str) 29244 (Ali CndashH str)

10944 (CndashN str)12298 (CndashO str) 16111 (C=C str)

120575537 (d 1H)120575215 (s 6H)120575126 (s 12H)

4754

8cCl

Cl NH2

C30H32Cl4O4N2 2333955 (OndashH str) 29279 (Ali CndashH str)

12566 (CndashO str) 16551 (C=C str)10946 (CndashN)

120575741 (s 1H)120575637 (s 1H)120575403 (d 4H)120575150 (s 4H)120575143 (s 12H)

6250

8d NH

C40H40O4N2 2732664 (OndashH str) 29408 (Ali CndashH str)

12516 (CndashO str) 16508 (C=C str)10291 (CndashN)

120575743 (m 22H)120575229 (s 6H)120575120 (s 12H)

6136

8e NH C23H37O4N2 36

3427 (OndashH str) 30207 (Ali CndashH str)12164 (CndashO str) 15627 (C=C str)

10411 (CndashN)

120575347 (m 4H)120575229 (s 4H)120575120 (s 12H)

4211

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Advances in Chemistry 7

were synthesized from different amines such as diethylamine34-dichlorobenzylamine dibenzylamine benzylamine andN-methyl piperazine These derivatives were synthesized bythe ring opening of epoxide and were identified by differentspectroscopic techniques [41] The synthesized compoundswere screened for antihypertensive activity and some of thesecompounds showed significant antihypertensive activityPhysical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe are summarized inTable 2 Physical and spectral analysis of 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-ben-zo-[12-b54-1198871015840]dipyran derivatives 8andashe are summarized inTable 3

4 Conclusion

The present study describes the synthesis and evaluation ofthe antihypertensive activity of novel 2288-tetramethyl-2378-tetrahydro-46-diamino-37-dihydroxy-67-epoxy-benzo-[12-b54-1198871015840]dipyran derivatives 7andashe and 8andashe Compounds7b 7c and 7d showed potent antihypertensive activity andcan constitute lead compounds Compounds 7a 8a and8c showed minimal antihypertensive activity while othercompounds showed moderate antihypertensive activity

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors would like to thank Institute of PharmacyNirma University Ahmedabad Gujarat India for providingcontinuous support and Krupanidhi College of PharmacyBangalore for providing necessary facilities for experimentalworkThe authors are also thankful to SAIF CDRI Lucknowfor spectral analysis of the synthesized compounds Theauthors are also thankful to Council of Scientific and Indus-trial Research (CSIR) India and Department of Science ampTechnology (DST) India for providing for financial support

References

[1] B Rudy ldquoDiversity and ubiquity of K+ channelsrdquo Neurosciencevol 25 pp 729ndash735 1988

[2] L Aguilar-Bryan C G Nichols S W Wechsler et al ldquoCloningof the 120573 cell high-affinity sulfonylurea receptor a regulator ofinsulin secretionrdquo Science vol 268 no 5209 pp 423ndash426 1995

[3] K S Atwal G J Grover S Z Ahmed et al ldquoCardioselectiveanti-ischemic ATP-sensitive potassium channel openersrdquo Jour-nal of Medicinal Chemistry vol 36 no 24 pp 3971ndash3974 1993

[4] F Dreyer ldquoPeptide toxins and potassium channelsrdquo Reviews ofPhysiology Biochemistry and Pharmacology vol 115 pp 93ndash1361990

[5] I Baczko I Lepran and J G Papp ldquoKATP channel modulatorsincrease survival rate during coronary occlusion-reperfusion in

anaesthetized ratsrdquo European Journal of Pharmacology vol 324no 1 pp 77ndash83 1997

[6] K S Atwal P Wang W L Rogers et al ldquoSmall molecule mito-chondrial F

1F0ATPase hydrolase inhibitors as cardioprotective

agents Identification of 4-(N-arylimidazole)-substituted ben-zopyran derivatives as selective hydrolase inhibitorsrdquo Journal ofMedicinal Chemistry vol 47 no 5 pp 1081ndash1084 2004

[7] A Noma ldquoATP-regulated K+ channels in cardiac musclerdquoNature vol 305 pp 147ndash148 1983

[8] A D Wickenden ldquoK+ channels as therapeutic drug targetsrdquoPharmacology ampTherapeutics vol 94 no 1-2 pp 157ndash182 2002

[9] S J H Ashcroft and F M Ashcroft ldquoProperties and functionsof ATP-sensitive K-channelsrdquo Cellular Signalling vol 2 no 3pp 197ndash214 1990

[10] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[11] J Anabuki M Hori H Ozaki I Kato and H Karaki ldquoMecha-nisms of pinacidil-induced vasodilatationrdquo European Journal ofPharmacology vol 190 no 3 pp 373ndash379 1990

[12] R H Grimm Jr ldquoAntihypertensive therapy taking lipids intoconsiderationrdquo The American Heart Journal vol 122 no 3 pp910ndash918 1991

[13] S L Archer J Huang T Henry D Peterson and E KWeir ldquoA redox-based O

2sensor in rat pulmonary vasculaturerdquo

Circulation Research vol 73 no 6 pp 1100ndash1112 1993[14] J Bellemin-Baurreau A Poizot P E Hicks L Rochette and

J Michael Armstrong ldquoEffects of ATP-dependent K+ channelmodulators on an ischemia-reperfusion rabbit isolated heartmodel with programmed electrical stimulationrdquo European Jour-nal of Pharmacology vol 256 no 2 pp 115ndash124 1994

[15] V M Bolotina ldquoCalcium-activated potassium channels incultured human endothelial cells are not directly modulated bynitric oxiderdquo Nature vol 368 pp 850ndash854 1994

[16] G Edwards and A H Weston ldquoThe pharmacology of ATP-sensitive potassium channelsrdquo Annual Review of Pharmacologyand Toxicology vol 33 pp 597ndash637 1993

[17] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[18] K Tanaka H Kawasaki K Kurata Y Aikawa Y Tsukamotoand T Inaba ldquoT-614 a novel antirheumatic drug inhibits boththe activity and induction of cyclooxygenase-2 (COX-2) incultured fibroblastsrdquo Japanese Journal of Pharmacology vol 67no 4 pp 305ndash314 1995

[19] E Tyrrell K H Tesfa I Greenwood and A Mann ldquoThesynthesis and biological evaluation of a range of novel function-alised benzopyrans as potential potassium channel activatorsrdquoBioorganic and Medicinal Chemistry Letters vol 18 no 3 pp1237ndash1240 2008

[20] J M Evans C S Fake T C Hamilton R H Poyserand G A Showell ldquoSynthesis and antihypertensive activityof 67-disubstituted trans-4-amino-34-dihydro-22-dimethyl-2H-1-benzopyran-3-olsrdquo Journal ofMedicinal Chemistry vol 27no 9 pp 1127ndash1131 1984

[21] G C Rovnyak S Z Ahmed C Z Ding et al ldquoCardioselectiveantiischemic ATP-sensitive potassium channel (KATP) openers5 Identification of 4-(N-aryl)-substituted benzopyran deriva-tives with high selectivityrdquo Journal of Medicinal Chemistry vol40 no 1 pp 24ndash34 1997

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

8 Advances in Chemistry

[22] H H Herman S H Pollock L C Fowler and S WMay ldquoDemonstration of the potent antihypertensive activityof phenyl-2-aminoethyl sulfidesrdquo Journal of CardiovascularPharmacology vol 11 no 5 pp 201ndash210 1988

[23] J L Wang K Aston D Limburg et al ldquoThe novel benzopyranclass of selective cyclooxygenase-2 inhibitors Part III thethreemicrodose candidatesrdquo Bioorganic ampMedicinal ChemistryLetters vol 20 no 23 pp 7164ndash7168 2010

[24] Y-M Lee M-H Yen Y-Y Peng et al ldquoThe antihypertensiveand cardioprotective effects of (minus)-MJ-451 an ATP-sensitive K+channel openerrdquoEuropean Journal of Pharmacology vol 397 no1 pp 151ndash160 2000

[25] N Kaur A Kaur Y Bansal D I Shah G Bansal andM SinghldquoDesign synthesis and evaluation of 5-sulfamoyl benzimida-zole derivatives as novel angiotensin II receptor antagonistsrdquoBioorganic and Medicinal Chemistry vol 16 no 24 pp 10210ndash10215 2008

[26] S Prasanna E Manivannan and S C Chaturvedi ldquoQuanti-tative structure-activity relationship analysis of a series of 23-diaryl benzopyran analogues as novel selective cyclooxygenase-2 inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol14 no 15 pp 4005ndash4011 2004

[27] A Bali Y Bansal M Sugumaran et al ldquoDesign synthesis andevaluation of novelly substituted benzimidazole compounds asangiotensin II receptor antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 17 pp 3962ndash3965 2005

[28] L Xing B C Hamper T R Fletcher et al ldquoStructure-basedparallel medicinal chemistry approach to improve metabolicstability of benzopyran COX-2 inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 21 no 3 pp 993ndash996 2011

[29] J Gierse M Nickols K Leahy et al ldquoEvaluation of COX-1COX-2 selectivity and potency of a new class of COX-2inhibitorsrdquo European Journal of Pharmacology vol 588 no 1pp 93ndash98 2008

[30] H J Finlay J Lloyd M Nyman et al ldquoPyrano-[23b]-pyridinesas potassium channel antagonistsrdquo Bioorganic and MedicinalChemistry Letters vol 18 no 8 pp 2714ndash2718 2008

[31] B Becker M-H Antoine Q-A Nguyen et al ldquoSynthesis andcharacterization of a quinolinonic compound activating ATP-sensitive K+ channels in endocrine and smooth muscle tissuesrdquoBritish Journal of Pharmacology vol 134 no 2 pp 375ndash3852001

[32] Y H Joo J K Kim S-H Kang et al ldquo23-Diarylbenzopyranderivatives as a novel class of selective cyclooxygenase-2inhibitorsrdquo Bioorganic and Medicinal Chemistry Letters vol 13no 3 pp 413ndash417 2003

[33] R Hong J Feng R Hoen and G-Q Lin ldquoSynthesis of (plusmn)-331015840-bis(4-hydroxy-2H-benzopyran) a literature correctionrdquoTetrahedron vol 57 no 41 pp 8685ndash8689 2001

[34] J Lim I-H Kim H H Kim K-S Ahn and H Han ldquoEnan-tioselective syntheses of decursinol angelate and decursinrdquoTetrahedron Letters vol 42 no 24 pp 4001ndash4003 2001

[35] M C Breschi V Calderone A Martelli et al ldquoNewbenzopyran-based openers of the mitochondrial ATP-sensitivepotassium channel with potent anti-ischemic propertiesrdquo Jour-nal ofMedicinal Chemistry vol 49 no 26 pp 7600ndash7602 2006

[36] T Takahashi H Koga H Sato T Ishizawa N Taka andJ-I Imagawa ldquoSynthesis and vasorelaxant activity of 2-fluoromethylbenzopyran potassium channel openersrdquo Bioor-ganic and Medicinal Chemistry vol 6 no 3 pp 323ndash337 1998

[37] H Cho S Katoh S Sayama et al ldquoSynthesis andselective coronary vasodilatory activity of 34-dihydro-

22-bis(methoxymethyl)-2H-1-benzopyran-3-ol derivativesnovel potassium channel openersrdquo Journal of MedicinalChemistry vol 39 no 19 pp 3797ndash3805 1996

[38] N Taka H Koga H Sato T Ishizawa T Takahashi and J-I Imagawa ldquo6-Substituted 22-bis(fluoromethyl)-benzopyran-4-carboxamide K+ channel openersrdquo Bioorganic and MedicinalChemistry vol 8 no 6 pp 1393ndash1405 2000

[39] R Thompson S Doggrell and J O Hoberg ldquoPotassium chan-nel activators based on the benzopyran substructure synthesisand activity of the C-8 substituentrdquo Bioorganic amp MedicinalChemistry vol 11 no 8 pp 1663ndash1668 2003

[40] R Mannhold G Cruciani H Weber et al ldquo6-Substituted ben-zopyrans as potassium channel activators synthesis vasodilatorproperties and multivariate analysisrdquo Journal of MedicinalChemistry vol 42 no 6 pp 981ndash991 1999

[41] J Renaud S F Bischoff T Buhl et al ldquoEstrogen receptor mod-ulators identification and structuremdashactivity relationships ofpotent ER120572-selective tetrahydroisoquinoline ligandsrdquo Journal ofMedicinal Chemistry vol 46 no 14 pp 2945ndash2951 2003

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of