research article synthesis and biological evaluation of...

Research ArticleSynthesis and Biological Evaluation of Some NovelDithiocarbamate Derivatives

Beguumlm Nurpelin SaLlJk1 Yusuf Oumlzkay1 Uumlmide Demir Oumlzkay2 and Huumllya Karaca Genccediler3

1 Department of Pharmaceutical Chemistry Faculty of Pharmacy Anadolu University 26470 Eskisehir Turkey2Department of Pharmacology Faculty of Pharmacy Anadolu University 26470 Eskisehir Turkey3 Department of Pharmaceutical Microbiology Faculty of Pharmacy Anadolu University 26470 Eskisehir Turkey

Correspondence should be addressed to Yusuf Ozkay yozkay70gmailcom

Received 29 July 2014 Accepted 9 September 2014 Published 13 October 2014

Academic Editor Xinyong Liu

Copyright copy 2014 Begum Nurpelin Saglık et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

18 novel dithiocarbamate derivatives were synthesized in order to investigate their inhibitory potency on acetylcholinesteraseenzyme and antimicrobial activity Structures of the synthesized compounds were elucidated by spectral data and elementalanalyses The synthesized compounds showed low enzyme inhibitory activity However they displayed good antimicrobial activityprofile Antibacterial activity of compounds 4a 4e and 4p (MIC= 25 120583gmL)was equal to that of chloramphenicol againstKlebsiellapneumoniae (ATCC 700603) and Escherichia coli (ATCC 35218) Most of the compounds exhibited notable antifungal activityagainst Candida albicans (ATCC 10231) Candida glabrata (ATCC 90030) Candida krusei (ATCC 6258) and Candida parapsilosis(ATCC 7330) Moreover compound 4a which carries piperidin-1-yl substituent and dimethylthiocarbamoyl side chain as variablegroup showed twofold better anticandidal effect against all Candida species than reference drug ketoconazole

1 Introduction

Alzheimerrsquos disease (AD) is a an age associated neurodegen-erative syndromewith clinical characteristic and pathologicalproperties as loss of neurons in certain brain regions leadingto deficiency of memory cognitive dysfunction behavioraldisturbances and deficits in activities of daily living whicheventually leads to death [1ndash3] Although the underlyingpathophysiological mechanisms are not clear AD is firmlyassociated with impairment in cholinergic pathway whichresults in reduced level of acetylcholine (Ach) that is hydrol-ysed by cholinesterases (ChE) in certain areas of brain [1 2 45] It is well known that there are two major forms of ChE inthe brain ofmammalsThese are acetylcholinesterase (AChE)and butyrylcholinesterase (BuChE) found in neurons andglial cells and in neuritic plaques and tangles in Alzheimerrsquosdisease (AD) patients [6]

Since the late 1970s the treatment of AD has proceededand trended to a transmitter replacement strategy Elevation

of acetylcholine levels in brain through the use of AChEinhibitors has been established as the most effective treat-ment strategy against AD [3 7] Therefore AChE andorBuChE inhibitors have been recognised as the drug ofchoice in management of AD [8] Several AChE inhibitorscalled as ldquocognitive enhancersrdquo are being investigated forthe symptomatic treatment of Alzheimerrsquos disease [2 7 8]These drugs increase the concentration of acetylcholine atthe neurotransmitter sites or acts by regulating activity atnicotinic receptors [2 4]

There are three important subsites in ChE anionic siteoxyanion hole and acyl pocket [9] Carbamates as pyridos-tigmine rivastigmine and physostigmine constitute a classof ChE inhibitors These compounds have been reported todirect their carbamate region towards the acyl pocket thatincludes esteratic site of the enzymeThis inhibition is subse-quently reversed upon decarbamylation (Figure 1) Howevercarbamates have a relatively short duration of action andlimited penetration to blood-brain barrier [10]

Hindawi Publishing CorporationJournal of ChemistryVolume 2014 Article ID 387309 9 pageshttpdxdoiorg1011552014387309

2 Journal of Chemistry

Acyl pocket

CAS

(a)

Acyl pocket

Active site ser

CAS

Rivastigmine

(b)

Figure 1 (a) Ligand binding sites in acetylcholinesterase Hydrophobic residues in the gorge are shown as orange sticks The surface ofthe protein is shown in cadetblue Acetylcholine (green sticks) is shown in the catalytic anionic site (CAS) 120587-Cation interactions andhydrogen bonds are shown as white dotted lines The acyl pocket residues are shown as brown sticks (b) Interaction between rivastigmineand acetylcholinesterase After hydrolysis rivastigmine shown as coral sticks releases the carbamate residue towards the acyl pocket andenzyme inhibition occurs Images were taken from the official web site of European Bioinformatics Institute

Dithiocarbamates have attracted a great deal of interestin medicinal chemistry due to the fact that new effectivecompounds can be gained by the bioisosteric replacementof carbamate moiety with dithiocarbamate moiety They arealso important pharmacophores because of their lipophilicitywhich is essential for the delivery of central nervous system(CNS) drugs to their site of action through the blood-brainbarrier [11ndash18] Thus evaluation of novel dithiocarbamatederivatives as potential AChE inhibitors will be rational

The treatment of infectious diseases still remains a crucialproblem because of the increasing number of multidrugresistant microbial pathogens In spite of a large number ofantibiotics and chemotherapeutics existing for therapeuticuse the emergence of antibiotic resistance developed inthe last decades has created a substantial medical need fornew classes of antibacterial agents A potential approach toovercome the resistance problem is to design novel agentswith a different mode of action [19 20]

In addition to their potential AChE inhibitory activ-ity dithiocarbamate derivatives are important compoundsin antimicrobial chemotherapy due to their antibacterialand antifungal properties First Miller and Elson [21] andKligman and Rosensweig [22] determined the activity ofdimethyl dithiocarbamate salts against several pathogenicfungi and commented on their possible application in humantherapy In the last decade dithiocarbamatemoiety combinedheterocyclic ring systems were studied widely and now thesecompounds form a promising group of novel antifungalagents [23]

Cyclic amines as piperidine piperazine and morpholinepossess antimicrobial importance and thus they are often sub-jected to new antimicrobial agents development studies Forinstance quinoline drugs as norfloxacin and ciprofloxacincarry piperazine nucleus and show broad antibacterial activ-ity spectrum [24] Linezolid used for the treatment of infec-tions caused by gram-positive bacteria includes morpholine

group [25ndash27] Piperidine based chemical entities with arylsubstituents have been documented as potent microbialagents [28 29]

On the basis of above findings in the present study wereport the synthesis and biological evaluation of some noveldithiocarbamate derivatives as probable anticholinesteraseand antimicrobial agents

2 Experiment

21 Materials All reagents were purchased from commer-cial suppliers and were used without further purificationMelting points were determined on an Electrothermal 9100melting point apparatus (Weiss-Gallenkamp LoughboroughUK) and were uncorrected IR spectra were recorded onShimadzu 8400 FT-IR spectrophotometer (Shimadzu TokyoJapan) 1H-NMRspectrawere recorded on aBruker 500MHzspectrometer (Bruker Billerica USA) Mass spectra wererecorded on a VG Quattro mass spectrometer (Agilent Min-nesota USA) Elemental analyses were performed on a LecoCHNS-932 analyser (Leco Michigan USA) The TLC wasperformed to monitor reactions on silica gel 60 F

254(Merck)

layer using petroleum ether ethyl acetate (3 1 vv) for thefirst and third reaction steps and petroleum ether ethylacetate (1 1 vv) for the second and fourth reaction steps(Scheme 1)

22General Procedure for 4-Substituted-1-nitrobenzene Deriv-atives (1andash1c) 4-Fluoro-1-nitrobenzene (424mL 004mol)K2CO3(552 g 004mol) appropriate cyclic secondary amine

(004mol) and DMF (10mL) were added into a vial (30mL)of microwave synthesis reactor (Anton-Paar Monowave 300Graz Austria) The reaction mixture was heated underconditions of 200∘C and 10 bars for 15min After cooling themixturewas poured into iced-water precipitated productwaswashed with water dried and recrystallized from ethanol

Journal of Chemistry 3

F

N

X

X

NH

N

X

N

X

HNCl

O

N

X

HNS

OR

S

NO2

NO2 NH2

1 2

3

+

(i) (ii)

(iii)(iv)

4andash4o

Scheme 1 The synthetic route for the preparation of dithiocarbamate derivatives Reagents and conditions (i) K2CO3 DMF microwave

irradiation 15min (ii) Zn powder 25 HClEtOH room temperature 1 h and then reflux for 1 h (iii) ClCH2COCl TEA THF ice bath and

then room temperature 1 h (iv) corresponding dithiocarbamic acid sodium salt acetone reflux for 12 h

23 General Procedure for 4-Substituted Aniline Deriva-tives (2andash2c) Corresponding 4-substituted-1-nitrobenzenederivative (1andash1c) (0035mol) was dissolved in ethanol(100mL) and 25 HCl (100mL) mixture Zinc powder(2275 g 035mol) was divided into ten equal portions(2275 g times 10) and each portion was added to the stirringsolution in 15min intervals Once the addition of the zinc wascompleted reactionmixture was refluxed for 1 h Hot solutionwas allowed to cool down poured into ice water and thenneutralized with 10 NaOH solution The precipitate wasextracted with chloroform (3 times 100mL) The extracts werecombined and filtered over anhydrous Na

2SO4 The solvent

was evaporated and the residue was recrystallized fromethanol to give the 4-substituted aniline derivatives (2andash2c)

24 General Procedure for 2-Chloro-N-(4-substituted-phenyl)acetamide (3andash3c) Appropriate 4-substituted aniline (2andash2c) (0022mol) and triethylamine (32mL 022mol) weredissolved in THF (100mL) This mixture was allowed to stiron an ice bath Chloroacetyl chloride (18mL 0022mol) inTHF (10mL) was added drop by drop After this stage thecontent was stirred for 1 h at room temperature THF wasevaporated and the product was recrystallized from ethanol

25 N-[(4-Substituted-phenyl)-2-substitutedthiocarbonylthio]acetamide Derivatives (4andash4s) The compounds 3andash3c(0001mol) were stirred with appropriate sodium salt of dith-iocarbamic acid (00011mol) in acetone (30mL) for 3 h Theprecipitated product was filtered washed with water andrecrystallized from ethanol to gain the title products 4andash4s

251 N-[4-(Piperidin-1-yl)phenyl]-2-(dimethylaminothiocar-bonylthio)acetamide (4a) IR (KBr) ]max (cmminus1) 3288 (NndashH) 1651 (C=O) 1217 (C=S) 821 (14-disubstituted benzene)1H-NMR (500MHz DMSO-d6) 151ndash162 (m 6H piperi-dine C

345ndashH) 305 (s 6H ndashN (CH

3)2) 341ndash347 (m 4H

piperidine C26ndashH) 417 (s 2H ndashCOCH

2) 687 (d 2H 119869 =

835Hz phenyl C35ndashH) 740 (d 2H 119869 = 854Hz phenyl

C26ndashH) 1000 (s 1H ndashNHCO) MS (ESI) (mz) [M + 1]+

33816 Anal Calcd for C16H23N3OS2 C 5694 H 687 N

1245 Found C 5663 H 685 N 1249

252 N-[4-(Piperidin-1-yl)phenyl]-2-(diethylaminothiocarbon-ylthio)acetamide (4b) IR (KBr) ]max (cmminus1) 3289 (NndashH)1659 (C=O) 1236 (C=S) 824 (14-disubstituted benzene) 1H-NMR (500MHz DMSO-d6) 131 (t 6H 119869 = 714Hz ndashN(CH

2CH3)2) 151ndash163 (m 6H piperidine C

345ndashH) 303

(q 4H 119869 = 721Hz ndashN(CH2CH3)2) 339ndash349 (m 4H


2) 688 (d 2H 119869 =




1149 Found C 5907 H 742 N 1150

253 N-[4-(Piperidin-1-yl)phenyl]-2-(pyrrolidin-1-yl-thiocar-bonylthio)acetamide (4c) IR (KBr) ]max (cm

minus1) 3291 (NndashH)1659 (C=O) 1236 (C=S) 822 (14-disubstituted benzene) 1H-NMR (500MHz DMSO-d6) 151ndash162 (m 6H piperidineC345

ndashH) 191ndash206 (m 4H pyrrolidine C34ndashH) 304ndash309

(m 4H pyrrolidine C25ndashH) 341ndash347 (m 4H piperidine


C26ndashH) 420 (s 2H ndashCOCH

2) 687 (d 2H 119869 = 831Hz

phenyl C35ndashH) 740 (d 2H 119869 = 839Hz phenyl C

26ndashH)

999 (s 1H ndashNHCO) MS (ESI) (mz) [M + 1]+ 36411 AnalCalcd for C

18H25N3OS2 C 5947 H 693 N 1156 Found

C 5922 H 691 N 1159

254N-[4-(Piperidin-1-yl)phenyl]-2-(piperidin-1-yl-thiocarbon-ylthio)acetamide (4d) IR (KBr) ]max (cmminus1) 3287 (NndashH)1659 (C=O) 1234 (C=S) 822 (14-disubstituted benzene)1H-NMR (500MHz DMSO-d6) 151ndash166 (m 12H 2 timespiperidine C

345ndashH) 304ndash308 (m 4H piperidine C

26ndashH)

341ndash347 (m 4H piperidine C26ndashH) 420 (s 2H ndashCOCH

2)

687 (d 2H 119869 = 836Hz phenyl C35ndashH) 740 (d 2H 119869 =

829Hz phenyl C26ndashH) 1001 (s 1H ndashNHCO) MS (ESI)

(mz) [M + 1]+ 37819 Anal Calcd for C19H27N3OS2 C

6044 H 721 N 1113 Found C 6070 H 719 N 1115

255 N-[4-(Piperidin-1-yl)phenyl]-2-(4-methylpiperidin-1-yl-thiocarbonylthio)acetamide (4e) IR (KBr) ]max (cm

minus1) 3291(NndashH) 1659 (C=O) 1234 (C=S) 822 (14-disubstituted ben-zene) 1H-NMR (500MHz DMSO-d6) 093 (d 3H 119869 =711Hz ndashCH

3) 150ndash164 (m 11H 2 times piperidine C

345ndash

H) 304ndash309 (m 4H piperidine C26ndashH) 341ndash346 (m 4H


2) 687 (d 2H 119869 =




1073 Found C 6142 H 745 N 1070

256 N-[4-(Piperidin-1-yl)phenyl]-2-(4-benzylpiperidin-1-yl-thiocarbonylthio)acetamide (4f) IR (KBr) ]max (cm

minus1) 3289(NndashH) 1659 (C=O) 1234 (C=S) 822 (14-disubstituted ben-zene) 1H-NMR (500MHz DMSO-d6) 144ndash163 (m 11H2 times piperidine C

345ndashH) 254 (d 2H 119869 = 714Hz

ndashCH2C6H5) 304ndash310 (m 4H piperidine C

26ndashH) 342ndash

348 (m 4H piperidine C26ndashH) 419 (s 2H ndashCOCH

2)

687 (d 2H 119869 = 822Hz phenyl C35ndashH) 719ndash731 (m 5H

ndashCH2C6H5) 741 (d 2H 119869 = 830Hz phenyl C

26ndashH) 1002

(s 1H ndashNHCO)MS (ESI) (mz) [M+ 1]+ 46817 Anal Calcdfor C26H33N3OS2 C 6677 H 711 N 898 Found C 6659

H 709 N 900

257 N-[4-(Morpholin-4-yl)phenyl]-2-(dimethylaminothiocar-bonylthio)acetamide (4g) IR (KBr) ]max (cmminus1) 3287 (NndashH) 1659 (C=O) 1234 (C=S) 822 (14-disubstituted benzene)1H-NMR (500MHz DMSO-d6) 304 (s 6H ndashN(CH

3)2)

341ndash347 (m 4H morpholine C35ndashH) 372ndash374 (m 4H

morpholine C26ndashH) 418 (s 2H ndashCOCH

2) 689 (d 2H

119869 = 832Hz phenyl C35ndashH) 744 (d 2H 119869 = 844Hz

phenyl C26ndashH) 1001 (s 1H ndashNHCO)MS (ESI) (mz) [M +

1]+ 34015 Anal Calcd for C15H21N3OS2 C 5307 H 624

N 1238 Found C 5333 H 625 N 1236

258 N-[4-(Morpholin-4-yl)phenyl]-2-(diethylaminothiocar-bonylthio)acetamide (4h) IR (KBr) ]max (cmminus1) 3289 (NndashH) 1659 (C=O) 1235 (C=S) 822 (14-disubstituted benzene)

1H-NMR (500MHz DMSO-d6) 123 (t 6H 119869 = 718Hz ndashN(CH

2CH3)2) 304 (q 4H 119869 = 716Hz ndashN(CH

2CH3)2)



2) 689 (d 2H

119869 = 833Hz phenyl C35ndashH) 745 (d 2H 119869 = 829Hz phenyl


36812 Anal Calcd for C17H25N3O2S2 C 5556 H 686 N

1143 Found C 5662 H 685 N 1141

259 N-[4-(Morpholin-4-yl)phenyl]-2-(pyrrolidin-1-yl-thiocar-bonylthio)acetamide (4i) IR (KBr) ]max (cm

minus1) 3287 (NndashH)1659 (C=O) 1234 (C=S) 822 (14-disubstituted benzene) 1H-NMR (500MHz DMSO-d6) 193ndash207 (m 4H pyrrolidineC34ndashH) 303ndash306 (m 4H pyrrolidine C

25ndashH) 341ndash348

(m 4Hmorpholine C35ndashH) 373ndash382 (m 4Hmorpholine


2) 689 (d 2H 119869 = 836Hz


26ndashH)


17H23N3O2S2 C 5586 H 634 N 1150 Found

C 5594 H 637 N 1151

2510 N-[4-(Morpholin-4-yl)phenyl]-2-(piperidin-1-yl-thiocar-bonylthio)acetamide (4j) IR (KBr) ]max (cm


ndashH) 303ndash306 (m 4H piperidine C26ndashH) 341ndash348



2) 689 (d 2H 119869 = 842Hz


26ndashH)


18H25N3O2S2 C 5696 H 664 N 1107 Found

C 5710 H 667 N 1108

2511N-[4-(Morpholin-4-yl)phenyl]-2-(4-methylpiperidin-1-yl-thiocarbonylthio)acetamide (4k) IR (KBr) ]max (cm


3) 150ndash165 (m 5H piperidine C

345ndashH)

303ndash309 (m 4H piperidine C26ndashH) 340ndash346 (m 4H

morpholine C35ndashH) 371ndash377 (m 4H morpholine C

26ndash

H) 419 (s 2H ndashCOCH2) 688 (d 2H 119869 = 831Hz phenyl

C35ndashH) 742 (d 2H 119869 = 839Hz phenyl C

26ndashH) 1002 (s

1H ndashNHCO) MS (ESI) (mz) [M + 1]+ 39418 Anal CalcdforC19H27N3O2S2 C 5798H 691N 1068 FoundC 5808

H 692 N 1069

2512 N-[4-(Morpholin-4-yl)phenyl]-2-(4-benzylpiperidin-1-yl-thiocarbonylthio)acetamide (4l) IR (KBr) ]max (cmminus1)3289 (NndashH) 1659 (C=O) 1233 (C=S) 822 (14-disubstitutedbenzene) 1H-NMR (500MHz DMSO-d6) 151ndash162 (m 5Hpiperidine C

345ndashH) 252 (d 2H 119869 = 722Hz ndashCH

2C6H5)



26ndash


C35ndashH) 719ndash731 (m 5H ndashCH

2C6H5) 741 (d 2H 119869 =



Table 1 Some physicochemical properties of the synthesized compounds

Comp X R Yield () Mp (∘C) Mp (∘C) [Lit] Molecular formula Molecular weight(gmol) Appearance

1a CH2 mdash 73 97 95 [31] C11H14N2O2 206 Yellow1b O mdash 69 161 158-159 [32] C10H12N2O3 208 Yellow1c NndashCH3 mdash 79 106 105-106 [33] C11H15N3O2 221 Yellow2a CH2 mdash 42 41 40 [34] C11H16N2 176 White2b O mdash 51 131 1295ndash1305 [35] C10H14N2O 178 Brown2c NndashCH3 mdash 49 92 93 [36] C11H17N3 191 White3a CH2 mdash 79 132 mdash C13H17ClN2O 2525 Brown3b O mdash 81 171 170ndash172 [37] C12H15ClN2O2 2545 Brown3c NndashCH3 mdash 76 186 mdash C13H18ClN3O 2675 Brown4a CH2 ndashN(CH3)2 75 142 mdash C16H23N3OS2 337 Cream-colored4b CH2 ndashN(C2H5)2 83 127 mdash C18H27N3OS2 365 Brown4c CH2 Pyrrolidin-1-yl 85 163 mdash C18H25N3OS2 363 Cream-colored4d CH2 Piperidin-1-yl 82 235 mdash C19H27N3OS2 391 Cream-colored4e CH2 4-Methylpiperidin -1-yl 79 212 mdash C20H29N3OS2 405 Brown4f CH2 4-Benzylpiperidin-1-yl 84 220 mdash C26H33N3OS2 481 Brown4g O ndashN(CH3)2 87 148 mdash C15H21N3OS2 339 Brown4h O ndashN(C2H5)2 78 97 mdash C17H25N3O2S2 367 White4i O Pyrrolidin-1-yl 73 175 mdash C17H23N3O2S2 365 Cream-colored4j O Piperidin-1-yl 77 171 mdash C18H25N3O2S2 393 Brown4k O 4-Methylpiperidin -1-yl 69 165 mdash C19H27N3O2S2 407 Cream-colored4l O 4-Benzylpiperidin-1-yl 72 150 mdash C25H31N3O2S2 483 Cream-colored4m NndashCH3 ndashN(CH3)2 70 185 mdash C16H24N4OS2 352 Brown4n NndashCH3 ndashN(C2H5)2 78 152 mdash C18H26N4OS2 380 White4o NndashCH3 Pyrrolidin-1-yl 73 175 mdash C19H28N4OS2 378 Cream-colored4p NndashCH3 Piperidin-1-yl 75 147 mdash C20H30N4OS2 406 Brown4r NndashCH3 4-Methylpiperidin-1yl 71 179 mdash C26H34N4OS2 420 Brown4s NndashCH3 4-Benzylpiperidin-1-yl 82 155 mdash C16H24N4OS2 496 Cream-colored

(mz) [M + 1]+ 47021 Anal Calcd for C25H31N3O2S2 C

6393 H 665 N 895 Found C 6375 H 663 N 898

2513 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(dimethylami-nothiocarbonylthio)acetamide (4m) IR (KBr) ]max (cmminus1)3273 (NndashH) 1654 (C=O) 1221 (C=S) 822 (14-disubstitutedbenzene) 1H-NMR (500MHz DMSO-d6) 222 (s 3H ndashNCH3) 306 (s 6H ndashN(CH

3)2) 339ndash357 (m 8H piper-

azine C2356

ndashH) 418 (s 2H ndashCOCH2) 688 (d 2H 119869 =




1589 Found C 5438 H 684 N 1584

2514 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(diethylamino-thiocarbonylthio)acetamide (4n) IR (KBr) ]max (cm

minus1) 3292(NndashH) 1654 (C=O) 1234 (C=S) 820 (14-disubstituted ben-zene) 1H-NMR (500MHz DMSO-d6) 123 (t 6H 119869 =711Hz ndashN(CH

2CH3)2) 224 (s 3H ndashNCH

3) 306 (q 4H

119869 = 716Hz ndashN(CH2CH3)2) 339ndash362 (m 8H piperazine

C2356

ndashH) 418 (s 2H ndashCOCH2) 688 (d 2H 119869 = 819Hz


26ndashH)


18H28N4OS2 C 5681 H 742 N 1472 Found C

5658 H 744 N 1475

2515 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(pyrrolidin-1-yl-thiocarbonylthio)acetamide (4o) IR (KBr) ]max (cmminus1)3287 (NndashH) 1654 (C=O) 1234 (C=S) 820 (14-disubstitutedbenzene) 1H-NMR (500MHz DMSO-d6) 206ndash210 (m4H pyrrolidine C

34ndashH) 222 (s 3H ndashNCH

3) 304ndash308

(m 4H pyrrolidine C25ndashH) 342ndash365 (m 8H piperazine

C2356



26ndashH)


18H26N4OS2 C 5711 H 692 N 1480 Found C

5742 H 694 N 1475

2516 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(piperidin-1-yl-thiocarbonylthio)acetamide (4p) IR (KBr) ]max (cm

minus1) 3291(NndashH) 1661 (C=O) 1234 (C=S) 820 (14-disubstituted ben-zene) 1H-NMR (500MHz DMSO-d6) 156ndash168 (m 6H


piperidine C345

ndashH) 224 (s 3H ndashNCH3) 303ndash308 (m 4H

piperidine C26ndashH) 341ndash368 (m 8H piperazine C

2356ndashH)

419 (s 2H ndashCOCH2) 688 (d 2H 119869 = 824Hz phenyl C

35ndash

H) 742 (d 2H 119869 = 831Hz phenyl C26ndashH) 1003 (s 1H

ndashNHCO) MS (ESI) (mz) [M + 1]+ 39313 Anal Calcd forC19H28N4OS2 C 5813 H 719 N 1427 Found C 5842 H

721 N 1425

2517 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(4-methylpipe-ridin-1-yl-thiocarbonylthio)acetamide (4r) IR (KBr) ]max(cmminus1) 3293 (NndashH) 1661 (C=O) 1234 (C=S) 820 (14-disubstituted benzene) 1H-NMR (500MHz DMSO-d6)096 (d 3H 119869 = 708Hz ndashCH

3) 152ndash165 (m 5H piperidine

C345


(m 8H piperazine C2356

ndashH) 419 (s 2H ndashCOCH2) 688

(d 2H 119869 = 826Hz phenyl C35ndashH) 741 (d 2H 119869 = 824Hz

phenyl C26ndashH) 1001 (s 1H ndashNHCO) MS (ESI) (mz) [M

+ 1]+ 40716 Anal Calcd for C20H30N4OS2 C 5908 H 744

N 1378 Found C 5922 H 746 N 1371

2518 N-[4-(4-Methylpiperazin-1-yl)phenyl]-2-(4-benzylpipe-ridin-1-yl-thiocarbonylthio)acetamide (4s) IR (KBr) ]max(cmminus1) 3275 (NndashH) 1659 (C=O) 1221 (C=S) 822 (14-disubstituted benzene) 1H-NMR (500MHz DMSO-d6)151ndash162 (m 5H piperidine C

345ndashH) 261 (d 2H 119869 =

716Hz ndashCH2C6H5) 305ndash309 (m 4H piperidine C

26ndash

H) 344ndash375 (m 8H piperazine C2356

ndashH) 418 (s 2HCOCH

2) 688 (d 2H 119869 = 811Hz phenyl C


(m 5H ndashCH2C6H5) 742 (d 2H 119869 = 827Hz phenyl C

26ndash

H) 1004 (s 1H NHCO) MS (ESI) (mz) [M + 1]+ 48315Anal Calcd for C

26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158

26 Enzymatic Assay All compounds were subjected to aslightly modified method of Ellmanrsquos test [30 31] in orderto evaluate their potency to inhibit the AChE Donepezilhydrochloride was used as a positive control (Table 2)Enzyme solutions were prepared in gelatin solution (1)at a concentration of 25 unitsmL AChE and compoundsolution (50 120583L) which is prepared in 2 DMSO at 01 and1mM concentrations were added to 30mL phosphate buffer(pH 8 plusmn 01) and incubated at 25∘C for 5min The reactionwas started by adding DTNB (50 120583L) and ATC (10 120583L) tothe enzyme-inhibitor mixture The production of the yellowanion was recorded for 10min at 412 nm As a control anidentical solution of the enzyme without the inhibitor isprocessed following the same protocol The blank readingcontained 30mL buffer 50 120583L 2 DMSO 50 120583L DTNB and10 120583L substrate All processes were assayed in triplicate Theinhibition rate () was calculated by the following equation

Inhibition =[(119860119862minus 119860119861) minus (119860

119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)

where 119860119868is the absorbance in the presence of the inhibitor

119860119862is the absorbance of the control and119860

119861is the absorbance

of blank reading Both of the values are corrected withblank-reading value SPSS for Windows 150 was used for

Table 2 Inhibition potency of the compounds on AChE at 10minus3ndash10minus4 M concentrations

Comp Inhibition 10minus3M 10minus4M

4a 1695 16454b 1621 14364c 4193 12984d 3139 9784e 4148 11474f 954 8374g 756 2424h 858 1974i 1556 1024j 1555 1494k 1211 3014l 631 3864m 947 2434n 1211 2174o 2881 9314p 3778 2364r 765 7434s 740 510Donepezil 9837 9231

statistical analysis Studentrsquos 119905-test was used for all statisticalcalculations Data were expressed as mean plusmn SD inactive inculture medium

27 Broth Microdilution Assay The antimicrobial activitiesof compounds were tested using the microbroth dilutionmethod [32] MIC readings were performed twice for eachchemical agent Final products were tested for their invitro growth inhibitory activity against Enterococcus faecalis(ATCC 29212) Pseudomonas aeruginosa (ATCC 27853)Klebsiella pneumoniae (ATCC 700603) Escherichia coli(ATCC 35218) Escherichia coli (ATCC 25923) Candidaalbicans (ATCC 10231) Candida glabrata (ATCC 90030)Candida krusei (ATCC 6258) and Candida parapsilosis(ATCC 7330) Chloramphenicol and ketoconazole were usedas control drugs

The cultures were obtained from Mueller-Hinton broth(Difco) for the bacterial strains after overnight incubation at35 plusmn 1∘C The yeasts were maintained in Sabouraud dextrosebroth (Difco) after overnight incubation 35plusmn 1∘CThe inoculaof test microorganisms were adjusted to match the turbidityof a MacFarland 05 standard tube as determined with aspectrophotometer and the final inoculum size was 05ndash25times 105 cfumL for antibacterial and antifungal assays Testingwas carried out in Mueller-Hinton broth and Sabourauddextrose broth (Difco) at pH 7 and the twofold serial dilutiontechnique was applied The last well on the microplatescontaining only inoculated broth was kept as controls andthe last well with no growth of microorganism was recordedto represent the MIC expressed in 120583gmL For both theantibacterial and antifungal assays the compounds were


Table 3 Antimicrobial activities of the compounds as MIC values (120583gmL)

Comp A B C D E F G H I4a 25 50 25lowast 25lowast 25lowast 25lowastlowast 25lowastlowast 25lowastlowast 25lowastlowast

4b 200 50 50 50 200 50lowast 25lowastlowast 50lowast 50lowast

4c 25 50 50 50 50 50lowast 50lowast 25lowastlowast 50lowast

4d 200 50 50 50 200 50lowast 50lowast 50lowast 25lowastlowast

4e 50 50 25lowast 25lowast 50 25lowastlowast 50lowast 25lowastlowast 50lowast

4f 25 50 50 50 50 50lowast 50lowast 50lowast 50lowast

4g 200 200 200 200 200 50lowast 50lowast 50lowast 2004h 50 50 50 50 200 200 100 400 4004i 200 200 200 200 200 400 50lowast 400 4004j 200 200 200 200 200 400 50lowast 400 4004k 200 50 50 50 200 400 50lowast 400 4004l 200 200 50 50 200 400 50lowast 400 2004m 200 50 50 50 200 400 50lowast 50lowast 2004n 200 200 50 50 50 400 50lowast 50lowast 2004o 200 50 50 50 200 400 50lowast 50lowast 2004p 200 200 25lowast 25lowast 200 400 50lowast 200 2004r 50 50 50 50 50 400 50lowast 400 50lowast

4s 200 200 50 50 200 400 100 200 400Ref-1 6125 25 25 25 25 mdash mdash mdash mdashRef-2 mdash mdash mdash mdash mdash 50 50 50 50A Enterococcus faecalis (ATCC 29212) B Pseudomonas aeruginosa (ATCC 27853) CKlebsiella pneumoniae (ATCC 700603) D Escherichia coli (ATCC 35218)E Escherichia coli (ATCC 25923) F Candida albicans (ATCC 10231) G Candida glabrata (ATCC 90030) H Candida krusei (ATCC 6258) and I Candidaparapsilosis (ATCC 7330) Ref-1 chloramphenicol Ref-2 ketoconazole lowastEqual activity to reference lowastlowastBetter activity than reference

dissolved in DMSO Further dilutions of the compounds andstandard drugs in test medium were prepared at the requiredquantities of 800 400 200 100 50 25 125 625 313 and163 120583gmL concentrations with Mueller-Hinton broth andSabouraud dextrose broth [32 33] Each experiment in theantimicrobial assays was replicated twice in order to definethe MIC values given in Table 1

3 Results and Discussion

In the present study some N-[(4-substituted-phenyl)-2-substitutedthiocarbonylthio]acetamide derivatives (4andash4s)were synthesized in order to evaluate their biological activ-ities Target compounds were prepared in four steps Initially4-fluoro-1-nitrobenzene in DMF was reacted with appro-priate cyclic secondary amine under microwave irradiationto obtain 4-substituted-1-nitrobenzene derivatives (1andash1c)In the second step nitro group reduction of 1andash1c gave 4-substituted aniline derivatives (2andash2c) which were acety-lated in further step by chloroacetyl chloride to gain 2-chloro-N-(4-substituted-phenyl)acetamides (3andash3c) Finallycompounds 3andash3c were reacted with appropriate dithiocar-bamic acid sodium salt to obtain target compounds (4andash4s)Synthetic route for the preparation of target compounds isoutlined in Scheme 1 Some physicochemical properties ofthe compounds are given in Table 1

Structure elucidations of the final compounds (4andash4s)were performedwith IR 1H-NMR and ES-MS spectroscopicmethods and elemental analysis Characteristic stretching

absorptions of C=O groups and NndashH bonds were observedat 1651ndash1661 cmminus1 and 3273ndash3493 cmminus1 respectively Thestretching absorptions at about 1230 cmminus1 were assigned toC=S bond In the 1H-NMR spectra all of the aromatic andaliphatic protons were observed at the estimated chemicalshifts The NndashH proton of the acetylamino group gave asinglet signal at 999ndash1006 ppm The aromatic protons of14-disubstituted phenyl ring were found at 687ndash745 ppmThe ndashCOCH

2protons appeared as singlet signals at 417ndash

421 ppm The M + 1 peaks in ES-MS spectra were inagreement with the calculated molecular weight of the targetcompounds (4andash4s) Elemental analysis results for C H andN elements were satisfactory within 04 calculated values ofthe compounds

The anticholinesterase effects of the compounds (4andash4s) were determined by modified Ellmanrsquos spectrophoto-metric method (Table 2) Donepezil was used as a standardAChE inhibitor The tested compounds showed low enzymeinhibitory activity However the compounds 4c and 4ewhich carry piperidine ring on fourth position of phenyldisplayed better inhibitory activity than other compounds

Contrary to their enzyme inhibitory potency synthesizedcompounds displayed good antimicrobialy activity profileAntibacterial activity of the compounds 4a 4e and 4p (MIC= 25 120583gmL) was equal to that of chloramphenicol againstKlebsiella pneumoniae (ATCC 700603) and Escherichia coli(ATCC 35218) Most of the compounds (4bndash4d 4f 4h 4kndash4o 4r and 4s) showedmoderate antibacterial activity againstthese two bacterial strains (Table 3)


N NH

O

S

S

N

Figure 2 Chemical structure of compound 4a

When compared with bacterial strain Candida specieswere found to be more sensitive to synthesized compoundsCompound 4a (Figure 2) which carries piperidin-1-yl sub-stituent and dimethylthiocarbamoyl side chain as variablegroups exhibited twofold better anticandidal effect than ref-erence drug ketoconazole Furthermore the other piperidin-1-yl substituted compounds 4bndash4f showed significant anti-fungal activity (Table 3) Although morpholin-4-yl and 4-methylpiperazin-1-yl substituted compounds 4gndash4l and 4mndash4s showed equal activity to reference drug against Candidaglabrata (ATCC 90030) their potency against the otherCandida species was not the samewith referenceThis findingsuggests that piperidin-1-yl substitution has good influenceon antifungal activity Besides dimethylthiocarbamoyl sidechain raises the antifungal activity significantly

4 Conclusion

In an effort to develop potent anticholinesterase and antimi-crobial agents we described the synthesis of a seriesof N-[(4-substituted-phenyl)-2-substitutedthiocarbonylthi-o]acetamide derivatives (4andash4s) and focused on their bio-logical activity evaluation Anticholinesterase activity of thesynthesized compounds was not as notable as antimicrobialactivity When compared with antibacterial activity targetcompounds displayed better antifungal effect profile Amongthese derivatives compound 4a can be identified as themost promising antifungal agent against all tested Candidaspecieswith a twofold lowerMICvalue (25 120583gmL) than keto-conazole This result may have a good impact on medicinalchemists to synthesize more active compounds that containsimilar chemical structure

Conflict of Interests

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

Acknowledgment

This study was financially supported by Anadolu UniversityScientific Research Projects Fund project no 1205S88

References

[1] W Thies and L Bleiler ldquo2012 Alzheimerrsquos disease facts andfiguresrdquo Alzheimerrsquos and Dementia vol 8 no 2 pp 131ndash1682012

[2] V Zarotsky J J Sramek and N R Cutler ldquoGalantaminehydrobromide an agent for Alzheimerrsquos diseaserdquo American

Journal of Health-System Pharmacy vol 60 no 5 pp 446ndash4522003

[3] J A Schneider Z Arvanitakis W Bang and D A BennettldquoMixed brain pathologies account for most dementia cases incommunity-dwelling older personsrdquo Neurology vol 69 no 24pp 2197ndash2204 2007

[4] A C Tricco S Vandervaart C Soobiah et al ldquoEfficacyof cognitive enhancers for Alzheimerrsquos disease protocol fora systematic review and network meta-analysisrdquo SystematicReviews vol 1 no 1 article 31 2012

[5] N Perry G Court N Bidet J Court and E Perry ldquoEuropeanherbs with cholinergic activities potential in dementia therapyrdquoInternational Journal of Geriatric Psychiatry vol 11 pp 1063ndash1069 1996

[6] C I Wright C Geula and M-M Mesulam ldquoNeuroglialcholinesterases in the normal brain and in Alzheimers diseaserelationship to plaques tangles and patterns of selective vulner-abilityrdquo Annals of Neurology vol 34 no 3 pp 373ndash384 1993

[7] S E Arnold and A Kumar ldquoReversible dementiasrdquo MedicalClinics of North America vol 77 pp 215ndash225 1993

[8] M Adams F Gmunder and M Hamburger ldquoPlants tra-ditionally used in age related brain disordersmdasha survey ofethnobotanical literaturerdquo Journal of Ethnopharmacology vol113 no 3 pp 363ndash381 2007

[9] J Takahashi I Hijikuro T Kihara et al ldquoDesign synthesisand evaluation of carbamate-modified (minus)-N1-phenethylnor-physostigmine derivatives as selective butyrylcholinesteraseinhibitorsrdquo Bioorganic amp Medicinal Chemistry Letters vol 20no 5 pp 1721ndash1723 2010

[10] C N Lieske R T Gepp J H Clark H G Meyer P Blum-bergs and C C Tseng ldquoAnticholinesterase activity of potentialtherapeutic 5-(13 3-trimethylindolinyl) carbamatesrdquo Journal ofEnzyme Inhibition vol 5 no 3 pp 215ndash223 1991

[11] P M Madalageri and O Kotresh ldquoSynthesis DNA protectionand antimicrobial activity of some novel chloromethyl ben-zimidazole derivatives bearing dithiocarbamatesrdquo Journal ofChemical and Pharmaceutical Research vol 4 no 5 pp 2697ndash2703 2012

[12] R B Silverman The Organic Chemistry of Drug Design andDrug Action Chapter 2 Elsevier Academic Press BurlingtonVt USA 2004

[13] H Waterbeemd and R Mannhold Lipophilicity descriptors forstructurendashproperty orrelation studies overview of experimentaland theoretical methods and a benchmark of log P calculationsLipophilicity in Drug Action and Toxicology chapter 23 VCHPublishers NewYork NY USA 1996

[14] R Tokuyama Y Takahashi Y Tomita et al ldquoStructure-activity relationship (SAR) studies on oxazolidinone antibacte-rial agents 21) Relationship between lipophilicity and antibac-terial activity in 5-thiocarbonyl oxazolidinonesrdquo Chemical andPharmaceutical Bulletin vol 49 no 4 pp 353ndash360 2001

[15] GA Patani and E J LaVoie ldquoBioisosterism a rational approachin drug designrdquo Chemical Reviews vol 96 no 8 pp 3147ndash31761996

[16] X-J Wang H-W Xu L-L Guo et al ldquoSynthesis and in vitroantitumor activity of new butenolide-containing dithiocarba-matesrdquo Bioorganic and Medicinal Chemistry Letters vol 21 no10 pp 3074ndash3077 2011

[17] K Bacharaju S R Jambula S Sivan S Jyostnatangeda and VManga ldquoDesign synthesis molecular docking and biologicalevaluation of new dithiocarbamates substituted benzimidazole


and chalcones as possible chemotherapeutic agentsrdquo Bioorganicamp Medicinal Chemistry Letters vol 22 no 9 pp 3274ndash32772012

[18] G Turan-Zitouni A Ozdemir and K Guven ldquoSynthesisof some 1-[(NN-disubstituted thiocarbamoylthio)acetyl]-3-(2-thienyl)-5-aryl-2-pyrazoline derivatives and investigation oftheir antibacterial and antifungal activitiesrdquo Archiv der Phar-mazie vol 338 no 2-3 pp 96ndash104 2005

[19] P Vicini A Geronikaki K Anastasia M Incerti andF Zani ldquoSynthesis and antimicrobial activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinonesrdquo Bioorganic andMedicinal Chemistry vol 14 no 11 pp 3859ndash3864 2006

[20] K H Chikhalia D B Vashi and M J Patel ldquoSynthesis of anovel class of some 134-oxadiazole derivatives as antimicrobialagentsrdquo Journal of Enzyme Inhibition and Medicinal Chemistryvol 24 no 3 pp 617ndash622 2009

[21] C R Miller andW O Elson ldquoDithiocarbamic acid derivativesthe relation of chemical structure to in vitro antibacterialand antifungal activity against human pathogensrdquo Journal ofBacteriology vol 57 no 1 pp 47ndash54 1949

[22] A M Kligman and W Rosensweig ldquoStudies with newfungistatic agents for the treatment of superficial mycosesrdquoTheJournal of Investigative Dermatology vol 10 no 2 pp 59ndash681948

[23] A C Karaburun Z A Kaplancıklı N Gundogdu-Karaburunand F Demirci ldquoSynthesis antibacterial and antifungal activi-ties of some carbazole dithiocarbamate derivativesrdquo Letters inDrug Design amp Discovery vol 8 pp 811ndash815 2011

[24] D C Hooper ldquoMode of action of fluoroquinolonesrdquoDrugs vol58 no 2 pp 6ndash10 1999

[25] E Wyrzykiewicz M Wendzonka and B Kedzia ldquoSynthe-sis and antimicrobial activity of new (E)-4-[piperidino (41015840-methylpiperidino- morpholino-) N-alkoxy]stilbenesrdquo Euro-pean Journal of Medicinal Chemistry vol 41 no 4 pp 519ndash5252006

[26] P P Dixit P S Nair V J Patil S Jain S K Arora and N SinhaldquoSynthesis and antibacterial activity of novel (un)substitutedbenzotriazolyl oxazolidinone derivativesrdquo Bioorganic andMedicinal Chemistry Letters vol 15 no 12 pp 3002ndash30052005

[27] P Panneerselvam R R Nair G Vijayalakshmi E H Subra-manian and S K Sridhar ldquoSynthesis of Schiff bases of 4-(4-aminophenyl)-morpholine as potential antimicrobial agentsrdquoEuropean Journal ofMedicinal Chemistry vol 40 no 2 pp 225ndash229 2005

[28] T Elavarasan D P Bhakiaraj and M Gopalakrishnan ldquoSyn-thesis spectral analysis in vitromicrobiological evaluation andmolecular docking studies of some novel 1-(1-aryl-1H-tetrazol-5-yl)-2-(piperidin-1-yl) ethanone derivativesrdquo ISRN OrganicChemistry vol 2014 Article ID 120173 9 pages 2014

[29] K Paulrasu A Duraikannu M Palrasu A Shanmugasun-daram M Kuppusamy and B Thirunavukkarasu ldquoSynthesisof 4-methyl-N1015840-(3-alkyl-2r6c-diarylpiperidin-4-ylidene)-123-thiadiazole-5-carbohydrazides with antioxidant antitumor andantimicrobial activitiesrdquo Organic amp Biomolecular Chemistryvol 12 no 31 pp 5911ndash5921 2014

[30] G L Ellman K D Courtney V Andres Jr and R MFeatherstone ldquoA new and rapid colorimetric determination ofacetylcholinesterase activityrdquo Biochemical Pharmacology vol 7no 2 pp 88ndash95 1961

[31] N S L Perry P J Houghton A Theobald P Jenner andE K Perry ldquoIn-vitro inhibition of human erythrocyte acetyl-cholinesterase by Salvia lavandulaefolia essential oil and con-stituent terpenesrdquo Journal of Pharmacy and Pharmacology vol52 no 7 pp 895ndash902 2000

[32] W Winn S Allen W Janda et al In Color Atlas and Textbookof Diagnostic Microbiology Lippincott Williams amp WilkinsBaltimore Md USA 6th edition 2006

[33] A Espinel-Ingroff ldquoIn vitro fungicidal activities of voricona-zole itraconazole and amphotericin B against opportunisticmoniliaceous and dematiaceous fungirdquo Journal of ClinicalMicrobiology vol 39 no 3 pp 954ndash958 2001

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


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


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


Acyl pocket

CAS

(a)

Acyl pocket

Active site ser

CAS

Rivastigmine

(b)

Figure 1 (a) Ligand binding sites in acetylcholinesterase Hydrophobic residues in the gorge are shown as orange sticks The surface ofthe protein is shown in cadetblue Acetylcholine (green sticks) is shown in the catalytic anionic site (CAS) 120587-Cation interactions andhydrogen bonds are shown as white dotted lines The acyl pocket residues are shown as brown sticks (b) Interaction between rivastigmineand acetylcholinesterase After hydrolysis rivastigmine shown as coral sticks releases the carbamate residue towards the acyl pocket andenzyme inhibition occurs Images were taken from the official web site of European Bioinformatics Institute

Dithiocarbamates have attracted a great deal of interestin medicinal chemistry due to the fact that new effectivecompounds can be gained by the bioisosteric replacementof carbamate moiety with dithiocarbamate moiety They arealso important pharmacophores because of their lipophilicitywhich is essential for the delivery of central nervous system(CNS) drugs to their site of action through the blood-brainbarrier [11ndash18] Thus evaluation of novel dithiocarbamatederivatives as potential AChE inhibitors will be rational

The treatment of infectious diseases still remains a crucialproblem because of the increasing number of multidrugresistant microbial pathogens In spite of a large number ofantibiotics and chemotherapeutics existing for therapeuticuse the emergence of antibiotic resistance developed inthe last decades has created a substantial medical need fornew classes of antibacterial agents A potential approach toovercome the resistance problem is to design novel agentswith a different mode of action [19 20]

In addition to their potential AChE inhibitory activ-ity dithiocarbamate derivatives are important compoundsin antimicrobial chemotherapy due to their antibacterialand antifungal properties First Miller and Elson [21] andKligman and Rosensweig [22] determined the activity ofdimethyl dithiocarbamate salts against several pathogenicfungi and commented on their possible application in humantherapy In the last decade dithiocarbamatemoiety combinedheterocyclic ring systems were studied widely and now thesecompounds form a promising group of novel antifungalagents [23]

Cyclic amines as piperidine piperazine and morpholinepossess antimicrobial importance and thus they are often sub-jected to new antimicrobial agents development studies Forinstance quinoline drugs as norfloxacin and ciprofloxacincarry piperazine nucleus and show broad antibacterial activ-ity spectrum [24] Linezolid used for the treatment of infec-tions caused by gram-positive bacteria includes morpholine

group [25ndash27] Piperidine based chemical entities with arylsubstituents have been documented as potent microbialagents [28 29]

On the basis of above findings in the present study wereport the synthesis and biological evaluation of some noveldithiocarbamate derivatives as probable anticholinesteraseand antimicrobial agents

2 Experiment

21 Materials All reagents were purchased from commer-cial suppliers and were used without further purificationMelting points were determined on an Electrothermal 9100melting point apparatus (Weiss-Gallenkamp LoughboroughUK) and were uncorrected IR spectra were recorded onShimadzu 8400 FT-IR spectrophotometer (Shimadzu TokyoJapan) 1H-NMRspectrawere recorded on aBruker 500MHzspectrometer (Bruker Billerica USA) Mass spectra wererecorded on a VG Quattro mass spectrometer (Agilent Min-nesota USA) Elemental analyses were performed on a LecoCHNS-932 analyser (Leco Michigan USA) The TLC wasperformed to monitor reactions on silica gel 60 F

254(Merck)

layer using petroleum ether ethyl acetate (3 1 vv) for thefirst and third reaction steps and petroleum ether ethylacetate (1 1 vv) for the second and fourth reaction steps(Scheme 1)

22General Procedure for 4-Substituted-1-nitrobenzene Deriv-atives (1andash1c) 4-Fluoro-1-nitrobenzene (424mL 004mol)K2CO3(552 g 004mol) appropriate cyclic secondary amine

(004mol) and DMF (10mL) were added into a vial (30mL)of microwave synthesis reactor (Anton-Paar Monowave 300Graz Austria) The reaction mixture was heated underconditions of 200∘C and 10 bars for 15min After cooling themixturewas poured into iced-water precipitated productwaswashed with water dried and recrystallized from ethanol


F

N

X

X

NH

N

X

N

X

HNCl

O

N

X

HNS

OR

S

NO2

NO2 NH2

1 2

3

+

(i) (ii)

(iii)(iv)

4andash4o





2SO4 The solvent






3)2) 341ndash347 (m 4H


2) 687 (d 2H 119869 =




1245 Found C 5663 H 685 N 1249



345ndashH) 303



2) 688 (d 2H 119869 =




1149 Found C 5907 H 742 N 1150







2) 687 (d 2H 119869 = 831Hz


26ndashH)


18H25N3OS2 C 5947 H 693 N 1156 Found

C 5922 H 691 N 1159



26ndashH)


2)




6044 H 721 N 1113 Found C 6070 H 719 N 1115




345ndash



2) 687 (d 2H 119869 =




1073 Found C 6142 H 745 N 1070



345ndashH) 254 (d 2H 119869 = 714Hz


26ndashH) 342ndash


2)



26ndashH) 1002


H 709 N 900


3)2)



2) 689 (d 2H




N 1238 Found C 5333 H 625 N 1236



2CH3)2) 304 (q 4H 119869 = 716Hz ndashN(CH

2CH3)2)



2) 689 (d 2H




1143 Found C 5662 H 685 N 1141






2) 689 (d 2H 119869 = 836Hz


26ndashH)


17H23N3O2S2 C 5586 H 634 N 1150 Found

C 5594 H 637 N 1151






2) 689 (d 2H 119869 = 842Hz


26ndashH)


18H25N3O2S2 C 5696 H 664 N 1107 Found

C 5710 H 667 N 1108




345ndashH)



26ndash



26ndashH) 1002 (s


H 692 N 1069



2C6H5)



26ndash



2C6H5) 741 (d 2H 119869 =







6393 H 665 N 895 Found C 6375 H 663 N 898



azine C2356





1589 Found C 5438 H 684 N 1584




3) 306 (q 4H


C2356



26ndashH)


18H28N4OS2 C 5681 H 742 N 1472 Found C

5658 H 744 N 1475



3) 304ndash308


C2356



26ndashH)


18H26N4OS2 C 5711 H 692 N 1480 Found C

5742 H 694 N 1475




piperidine C345



2356ndashH)


35ndash



721 N 1425



C345







N 1378 Found C 5922 H 746 N 1371


345ndashH) 261 (d 2H 119869 =


26ndash



2) 688 (d 2H 119869 = 811Hz phenyl C



26ndash


26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158



119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)































N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


F

N

X

X

NH

N

X

N

X

HNCl

O

N

X

HNS

OR

S

NO2

NO2 NH2

1 2

3

+

(i) (ii)

(iii)(iv)

4andash4o





2SO4 The solvent






3)2) 341ndash347 (m 4H


2) 687 (d 2H 119869 =




1245 Found C 5663 H 685 N 1249



345ndashH) 303



2) 688 (d 2H 119869 =




1149 Found C 5907 H 742 N 1150







2) 687 (d 2H 119869 = 831Hz


26ndashH)


18H25N3OS2 C 5947 H 693 N 1156 Found

C 5922 H 691 N 1159



26ndashH)


2)




6044 H 721 N 1113 Found C 6070 H 719 N 1115




345ndash



2) 687 (d 2H 119869 =




1073 Found C 6142 H 745 N 1070



345ndashH) 254 (d 2H 119869 = 714Hz


26ndashH) 342ndash


2)



26ndashH) 1002


H 709 N 900


3)2)



2) 689 (d 2H




N 1238 Found C 5333 H 625 N 1236



2CH3)2) 304 (q 4H 119869 = 716Hz ndashN(CH

2CH3)2)



2) 689 (d 2H




1143 Found C 5662 H 685 N 1141






2) 689 (d 2H 119869 = 836Hz


26ndashH)


17H23N3O2S2 C 5586 H 634 N 1150 Found

C 5594 H 637 N 1151






2) 689 (d 2H 119869 = 842Hz


26ndashH)


18H25N3O2S2 C 5696 H 664 N 1107 Found

C 5710 H 667 N 1108




345ndashH)



26ndash



26ndashH) 1002 (s


H 692 N 1069



2C6H5)



26ndash



2C6H5) 741 (d 2H 119869 =







6393 H 665 N 895 Found C 6375 H 663 N 898



azine C2356





1589 Found C 5438 H 684 N 1584




3) 306 (q 4H


C2356



26ndashH)


18H28N4OS2 C 5681 H 742 N 1472 Found C

5658 H 744 N 1475



3) 304ndash308


C2356



26ndashH)


18H26N4OS2 C 5711 H 692 N 1480 Found C

5742 H 694 N 1475




piperidine C345



2356ndashH)


35ndash



721 N 1425



C345







N 1378 Found C 5922 H 746 N 1371


345ndashH) 261 (d 2H 119869 =


26ndash



2) 688 (d 2H 119869 = 811Hz phenyl C



26ndash


26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158



119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)































N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



2) 687 (d 2H 119869 = 831Hz


26ndashH)


18H25N3OS2 C 5947 H 693 N 1156 Found

C 5922 H 691 N 1159



26ndashH)


2)




6044 H 721 N 1113 Found C 6070 H 719 N 1115




345ndash



2) 687 (d 2H 119869 =




1073 Found C 6142 H 745 N 1070



345ndashH) 254 (d 2H 119869 = 714Hz


26ndashH) 342ndash


2)



26ndashH) 1002


H 709 N 900


3)2)



2) 689 (d 2H




N 1238 Found C 5333 H 625 N 1236



2CH3)2) 304 (q 4H 119869 = 716Hz ndashN(CH

2CH3)2)



2) 689 (d 2H




1143 Found C 5662 H 685 N 1141






2) 689 (d 2H 119869 = 836Hz


26ndashH)


17H23N3O2S2 C 5586 H 634 N 1150 Found

C 5594 H 637 N 1151






2) 689 (d 2H 119869 = 842Hz


26ndashH)


18H25N3O2S2 C 5696 H 664 N 1107 Found

C 5710 H 667 N 1108




345ndashH)



26ndash



26ndashH) 1002 (s


H 692 N 1069



2C6H5)



26ndash



2C6H5) 741 (d 2H 119869 =







6393 H 665 N 895 Found C 6375 H 663 N 898



azine C2356





1589 Found C 5438 H 684 N 1584




3) 306 (q 4H


C2356



26ndashH)


18H28N4OS2 C 5681 H 742 N 1472 Found C

5658 H 744 N 1475



3) 304ndash308


C2356



26ndashH)


18H26N4OS2 C 5711 H 692 N 1480 Found C

5742 H 694 N 1475




piperidine C345



2356ndashH)


35ndash



721 N 1425



C345







N 1378 Found C 5922 H 746 N 1371


345ndashH) 261 (d 2H 119869 =


26ndash



2) 688 (d 2H 119869 = 811Hz phenyl C



26ndash


26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158



119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)































N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






6393 H 665 N 895 Found C 6375 H 663 N 898



azine C2356





1589 Found C 5438 H 684 N 1584




3) 306 (q 4H


C2356



26ndashH)


18H28N4OS2 C 5681 H 742 N 1472 Found C

5658 H 744 N 1475



3) 304ndash308


C2356



26ndashH)


18H26N4OS2 C 5711 H 692 N 1480 Found C

5742 H 694 N 1475




piperidine C345



2356ndashH)


35ndash



721 N 1425



C345







N 1378 Found C 5922 H 746 N 1371


345ndashH) 261 (d 2H 119869 =


26ndash



2) 688 (d 2H 119869 = 811Hz phenyl C



26ndash


26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158



119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)































N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


piperidine C345



2356ndashH)


35ndash



721 N 1425



C345







N 1378 Found C 5922 H 746 N 1371


345ndashH) 261 (d 2H 119869 =


26ndash



2) 688 (d 2H 119869 = 811Hz phenyl C



26ndash


26H34N4OS2 C 6469 H 710 N 1161

Found C 6477 H 712 N 1158



119868minus 119860119861)]

(119860119862minus 119860119861)

times 100 (1)































N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





















N NH

O

S

S

N



4 Conclusion




Acknowledgment


References














































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

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