[00] title pages and new index -...

INTRODUCTION, BIOLOGICAL SIGNIFICANCE

AND CHEMISTRY OF THE REACTIONS

INVOLVED IN

• SCHIFF BASE • THIAZOLIDINONE • AZATIDINONE • PYRIMIDINES

CCHHAAPPTTEERR 22

SYNTHESIS AND CHARACTERISATION OF SOME NEW SULPHUR BASED HETEROCYCLES

Page : 15

CHEMISTRY OF THE SCHIFF BASE

Schiff bases, named for Hugo Schiff, are formed when any primary amine

reacts with an aldehyde or a ketone under specific conditions. They are organic

compounds with the general formula RR′C═NR″, where R and R′ represent hydrogen,

an alkyl or an aryl and R″ is an alkyl or aryl; in the latter case, Schiff bases are also

called anils. Schiff bases are crystalline or oily substances that are insoluble in water

and soluble in organic solvents. They are weak bases, forming salts with acids in an

anhydrous medium; in aqueous acid solutions they undergo hydrolysis to yield an

amine and aldehyde. The majority of Schiff bases are stable in alkaline solutions.

Schiff bases undergo hydrogenation to give secondary amines (RR ′CH-NHR″) and

add on many compounds containing mobile hydrogen, such as β-dicarbonyl

compounds, ketones, and imines. They are produced mainly by the condensation of

aldehydes or ketones with primary amines. The reaction was first completed by H.

Schiff in 1864 (hence the name of the compounds). Schiff bases are valuable

intermediate products of organic synthesis, for example, in the preparation of

secondary amines and various heterocyclic compounds. The Schiff bases known as

azomethine dyes are used for dyeing acetate and synthetic fibers; they are also used in

color photography to reduce the photosensitivity of photographic emulsions.

Structurally, a Schiff base (also known as imine or azomethine) is a nitrogen

analogue of an aldehyde or ketone in which the carbonyl group has been replaced by

an imine or azomethine group [1], Many methods for the synthesis of Schiff bases [2-

4] have been developed and the simplest method appears is to condense by boiling

them into alcohols. Aldehydes and ketones react with primary amine (R-NH2) and

with other ammonia derivatives (Z-NH2) to form Schiff base (imine). An imine is a

compound with a carbon-nitrogen double bond (-CH=N-).

[I] [II]

Schiff bases are some of the most widely used organic compounds. They are

used as pigments and dyes, catalysts, intermediates in organic synthesis, and polymer

stabilizers.


Page : 16

BIOLOGICAL SIGNIFICANCE:

Schiff bases have also been shown to exhibit a broad range of biological

activities including antimicrobial [5-17], anti-inflammatory [18-22], analgesic [22],

anti-tubercular [23-25], antimycobacterial [26, 27], antioxidant [28], antiviral [29] and

inhibitors [30].

Thiacetazone and Nitrofyrazone are the drugs which have Schiff base in their

structures which are responsible for their biological activities.

Thiacetazone

Nitrofyrazone

Dimmock et al have synthesized acetylhydrazones [III] provided good

protection against convulsions while the oxamoylhydrazones [IV] were significantly

less active [31].

a

[III] [IV]

4-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in

the mammalian brain. GABA hydrazones [V] were synthesized and evaluated for

their anticonvulsant properties in different animal models by Ragavendran et al [32].

[V]

Lima and coworkers have synthesized [(4-N, N-dimethylamino benzylidene-3-

(3, 4-methylenedioxyphenyl) propionyl hydrazine] [VI] was more potent than

dipyrone and indomethacine are used as standard anti-inflammatory / antinociceptive

drugs [33].


Page : 17

[VI]

Kucukguzel and coworkers have synthesized N’-(4-methoxybenzamido)

benzoyl] a-N2-[(5-nitro-2-furyl)methylene]hydrazine [VII] inhibited the growth of

several bacteria and fungi [34].

[VII]

Turan-Zitouni et al have prepared some 5-bromoimidazo[1, 2-a]pyridine-2-

carboxylic acid benzylidenehydrazide [VIII] and screened their antimicrobial activity

[35].

[VIII]

Mamolo and coworkers have synthesized [5-(pyridine-2-yl)-1, 3, 4-thidiazole-

2-yl]acetic acid (3, 4-diaryl-3H-thiazole-2-ylidene)hydrazide [IX] and tested for their

in vitro anti mycobacterial activity [36].

[IX]

Sinha and coworkers have synthesized N-arylidene-N-[2-oxo-2-(4-aryl-

piperazin-1-yl) ethyl] hydrazide derivatives [X] containing isonicotinic acid

hydrazide-hydrazones and evaluated their anti mycobacterial activity [37].


Page : 18

[X]

Various diclofenac acid hydrazones [XI] were synthesized and evaluated for

their in vitro and in vivo anti mycobacterial activities by Sri ram et al [38].

[XI]

Terzioglu and Gursoy have synthesized some novel 2, 6-dimethyl-N’-

substituted – phenylmethyleneimidazo [2, 1 – b] [1, 3, 4] thiadiazole – 5 -

carbohydrazides [XII] showed the most favorable cytotoxicity [39].

[XII]

Demirbas et al have synthesized new hydrazide-hydrazones containing 5-oxo-

[1, 2, 4] triazole ring [XIIIa] and studied their antitumor activity in breast cancer [40].

[XIIIa]

Gursoy and Guzeldemirci-Ulusoy have synthesized 6-amino-4-aryl-2-oxo-1-

(1-pyrid-3-yl- or 4-yl-ethylidene-amino)-1, 2-dihydro pyridine-3, 5-dicarbo-nitrile

[XIIIb] and studied their antitumor activity [41].


Page : 19

[XIIIb]

Schiff bases derived from 2-[(2, 6-dichloroanilino) phenyl] acetic acid

(diclofenac acid) [XIV] were synthesized and studied for their anti inflammatory,

analgesic and ulcerogenicity activites by Bhandari et al [42].

[XIV]

Valentina et al have synthesized Some substituted 1, 2, 4 - triazo-5-thione

Schiff base [XV] and studied their antioxidant activity [43].

[XV]

Bawa and Kumar have synthesized Schiff base of 8-methyl-tetrazolo[1, 5-a]

quinoline [XVI] and evaluated their anti-inflammatory and antimicrobial activities

[44].

[XVI]

A series of sulfapyridine-polyhydroxyalkylidene (or arylidene)-imino

derivatives [XVII] have been prepared and reported for antitumor activity by Kamel

et al [45].

[XVII]


Page : 20

Schiff base of 4-(2-aminophenyl)-morpholines [XVIII] have been synthesized

and studied for their analgesic, anti-inflammatory, antibacterial and antifungal

activities by Panneerselvam and his co-workers [46].

[XVIII]

Kamal Vashi and H. B. Naik [47] have prepared a series of 2-hydroxy-3-

chloro-5-ethyl-N-(p-tolyl)-chalconimines [XIX]. The synthesized schiff bases were

screened for their antibacterial activity.

NCl OH

CH3

CH3(IV)

[XIX]

Santosh Kumar et al. [48] have studied the antimicrobial activity of the schiff

bases of sulfonamides. Among these schiff bases of sulphanilamide, compound

bearing trimethoxy group [XX] and furan ring [XXI] has shown good activity.

S

O

O

NH2N

O

O

O

CH3

CH3

CH3

S

O

O

NH2N

O

(V) (VI) [XX] [XXI]

Michael J. Hearn et al. [49] have prepared isoniazid schiff base [XXII] which

displayed good activity against M. tuberculosis.

N

O

NHN

(XI) [XXII]

A series of novel schiff bases of isatin was synthesized and anticonvulsant

activities have been screened by Chinnasamy Rajaram Prakash et al. [50]. Among the

compounds synthesized, [XXIII] showed excellent anticonvulsant activity.


Page : 21

NH

O

N

N

O

O

O CH3

CH3

CH3 [XXIII]

Synthesis and in vitro anti-HIV activity of some new schiff base ligands

derived from 5-amino-4-phenyl-4h-1, 2, 4-triazole-3-thiol has been reported by Najim

A. Al-Masoudi et al. [51] some of the synthesized compound [XXIV] were found to

be the most active inhibitors in cell culture against HIV-1.

N

N

N

SH

N

R

[XXIV]

P. Valentina and co workers [52] have ssynthesized a series of schiff bases of

3-substituted 1, 2, 4 triazo -5 thione. All the compounds were evaluated for its

antioxidant activity by hydrogen peroxide scavenging method. The result showed that

compound [XXV] has significant antioxidant activity.

N

N N

SHN

Ar

[XXV]


Page : 22

GENERAL METHODS FOR THE SYNTHESIS OF

SCHIFF BASE: M. C. Sharma, N. K. Sahu et al [53] have reported new N-(5-methyl-4-oxo-

thiazolidin-3-yl)-nicotinamide which have been synthesized by condensation of

nicotinic acid hydrazide with various aromatic or heterocyclic aldehydes to yield the

schiff bases and also synthesized 4-thiazolidinone derivatives by cyclo condensation

of schiff bases with 2-mercaptopropionic acid in dioxane.

N

O

NH NH2

N

O

NH N

R

N O

NH N

R

S

CH3

O

R - CHO Dry dioxane

2-mercaptopropionic acid Sie-Tiong Ha et al [54]. have mentioned the synthesis of new mesogenic schiff

base esters with polar chloro substituent using ethanol and aliphatic acid with the

catalytic amount of DDC.

NH2OH

O

OHCl+

Cl

NR - COO

1. Et OH, reflux

2. R - COOH,DMAP DCC

4, 4’-diaminodiphenylsulphone was condensed with various aromatic or

heterocyclic aldehyde in ethanol in the presence of concentrated sulphuric acid as a

catalyst to yield the schiff base has been reported by S. J. Wadher, M. P. Puranik et al.

[55].

NH2 S

OH

OH

NH2+O

R

R

R

N S

OH

OH

N

R= Arom at ic Aldehyde

H2SO4

EtOH

Arshi Naqvi and co worker[56] have mentioned the non classical methods like

water based reaction, microwave synthesis for the preparation of schiff bases using 3-

chloro-4-fluoro aniline and several benzaldehydes. These methodologies constitute an

energy-efficient and environmentally benign greener chemistry version for schiff

bases formation. O

ClF

NH2

R+

N

Cl

FR

M.W

Nuray Ulusoy Güzeldemirci and co workers [57] have discovered very simple

route for the preparation of thiazolidinone. The reaction of 1- (α, α-diphenyl-α-


Page : 23

hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate in the presence of sodium acetate -4-thiazolidinone derivatives.

Hai Jian Yang et al. [58] and Zhaoqi Yang et al.[59] have discovered a microwave-assisted preparation of a schiff-base. The efficient condensation of salicylaldehyde and aryl amines without solvent as a part of environmental friendship reaction in organic synthesis.

O

OH

Ar NH2+NH

OH

ArM.W.

New schiff bases derived from 2-aminopyridene and 2-aminopyrazine have

been synthesized using salicylaldehide and different heterocyclic amine in ethanol by Abdullah M. Asiri et al.[60]

X

N NH2 OH

O

+

OH

X

N N

EtOH,

Reflux

X= C, N A. M. Lopez-Periago et al. [61] have synthesised schiff base macrocycles

using supercritical CO2 as both solvent and acid catalyst. The preparation of trianglimines and schiff base has been successfully achieved using diamino cyclohexane and aromatic dialdehyde.

NH2

NH2

O

O

+CO2

N

N

N

N

N

N


Page : 24

REACTION MECHANISM:

R-CHO + H2N- R’ R-_CH = N- R’ + H2O

Addition of amine is carried out under mild acid catalysis to yield

an aldehyde. The acid catalyst protonates the carbonyl oxygen and

promoted the attack of nucleophillic amines.

R

H

O +

H

O+

HR

H

O

H

NH2

R'

..

R

H

OH

NH

H

R

R'+

R

R'

H

OH

NH

+ H

- H+

+

(Adduct product)

The adduct formed in this reaction undergoes a further reaction to

eliminate water and form a carbon nitrogen double bond.

H

N R'R

H

N+

H

..

R

H

NH

OH2 R

R'

R

R'

H

OH

NH

..

..

R'

..

+

H +

- H2O

- H


Page : 25

Reference: 1. Schiff H.; Arm. Chem., 137, 118 (1846).

2. Tipson R., Stuaret and Clapp M.A.; J. Org. Chem., 11, 292 (1946).

3. Hages K., Gener G. and Orchut J.; J. Am. Chem. Soc., 72, 1205 (1950).

4. Giovambattista N.S. and Rabassa R.; Chem. Abstr., 49, 205f (1955).

5. Panneerselvam P., Nair R.R., Vijayalakshmi G., Subramanian E.H. and

Sridhar S.K.; Eur. J. Med. Chem., 40, 225. (2005).

6. Karthikeyan M.S., Prasad D.J., Poojary B., Bhat K.S., Holla B.S. and Kumari

N.S.; Bioorg. Med. Chem., 14, 7482. (2006).

7. Shi L., Ge H., Tan S., Li H., Song Y., Zhu H. and Tan R.; Eur. J. Med. Chem.,

42, 558 (2007).

8. Sahu S.K., Azam M.A., Banerjee M., Acharrya S., Behera C.C. and Si S.; J.

Braz. Chem. Soc., 19, 963. (2008).

9. Onkol T., aGokçe M., Tosun A., Polat aS., Serin M. S. and Tezcan S.; Turk J.

Pharm. Sci., 5, 155, (2008)..

10. Satyanarayana V.S.V., Sreevani P., Sivakumar A. and Vijayakumar V.;

Arkivoc, 17, 221. (2008).

11. Panneerselvam P., Rathera B.A., Reddy D.R. and Kumar N.R.; Eur. J. Med.

Chem., 44, 2328. (2009).

12. Isloor A.M., Kalluraya B. and Shetty P.; Eur. J. Med. Chem., 44, 3784 (2009).

13. Wadher S. J., Puranika M.P., Karande N.A. and Yeole P. G.; Int. J. Pharm.

Res., 1, 22. (2009).

14. Bairagi S., Bhosale A. and Deodhar M.N.; E. J. Chem., 6, 759. (2009).

15. Vora J.J., Vasava S.B., Parmar K.C., Chauhan S.K. and Sharma S.S.; E- J.

Chem., 6, 1205. (2009).

16. Sonmez M., Celebi M. and Berber I.; Eur. J. Med. Chem., 45, 1935 (2010).

17. Miniyar P.B. and Makhija S.J; J. Young Pharm., 1, 165. (2010).

18. Narayana B., Ashalatha B.V., Raj K.K.V. and Kumari N.S.; Ind. J. Chem.,

45B, 2696 (2006).

19. Salgın-Goksen U., Gokhan-Kelekc N., Goktas O., Koysala Y., Kilic E., Isik

S., Aktay G. and Ozalp M.; Bioorg. Med. Chem., 15, 5738. (2007).

20. Kumar A., Rajput C. and Bhati S.; Bioorg. Med. Chem., 15, 3089, (2007)


Page : 26

21. Lin S., Tsai W., Chiou W., Yanga T. and Yanga L.; Bioorg. Med. Chem., 16,

2697 (2008).

22. Sondhi S.M., Singh N., Kumar A., Lozach O. and Meijer L.; Bioorg. Med.

Chem. 14, 3758. (2006).

23. Sinha N., Jain S., Tilekar A., Upadhayaya R.S., Kishore N., Jana G.H. and

Arora S.K.; Bioorg. Med. Chem. Lett., 15, 1573. (2005).

24. Gemmaa S., Savini L., Altarelli M., Tripaldi P., Chiasserini L., Coccone S. S.,

Kumar V., Camodeca C., Campiani G., Novellinoa E., Clarizio S., Delogu G.

and Butini S.; Bioorg. Med. Chem., 17, 606. (2009).

25. Hearn M. J., Cynamon M.H., Chen M.F., Coppins R., Davis J., Kanga H.J.,

Noble A., Tu-Sekine B., Terrot M.S., Trombino D., Thai M., Webster E.R.

and Wilson R.; Eur. J. Med. Chem., 44, 4169. (2009).

26. Patole J., Shingnapurkar D., Padhyea S. and Ratledge C.; Bioorg. Med. Chem.

Lett., 16, 1514, (2006).

27. Raparti V., Chitre T., Bothara K., Kumar V., Dangre S., Khachane C., Gore S.

and Deshmane B.; Eur. J. Med. Chem., 44, 3954. (2009).

28. Cheng L., Tang J., Luo H., Jin X., Dai F., Yang J., Qian Y., Li X. and Zhou

B.; Bioorg. Med. Chem. Lett., 20, 2417. (2010).

29. Jarrahpour A., Khalili D., Clercq E.D., Salmi C. and Brunel J.M.; 12, 1720

(2007).

30. Khan K.M., Ambreen N., Hussain S., Perveen S.and Choudhary M. I.; Bioorg.

Med. Chem., 17, 2983. (2009).

31. Dimmock J.R., Vashishtha S.C. and Stables J.P.; Eur. J. Med. Chem., 35, 241

(2000).

32. Ragavendran J., Sriram D., Patel S., Reddy I., Bharathwajan N., Stables J. and

Yogeeswari P.; Eur. J. Med. Chem., 42, 146, (2007).

33. Lima P.C., Lima L.M., Silva K.C., Leda P.H., Miranda A.L.P., Fraga C.A.M.

and Barreiro E.J.; Eur. J. Med. Chem., 35, 187, (2000).

34. Kucukguzel S.G., Oruc E.E., Rollas S., Sahin F. and Ozbek A.; Eur. J. Med.

Chem., 37, 197, (2002).

35. Turan-Zitouni G., Blache Y. and Guven K.; Bull. Chim. Farm., 140, 397

(2001).

36. Mamolo M.G., Falagiani V., Zampieri D., Vio L., Banfi E. and Scialino G.; Il

Farmaco, 58, 631, (2003).


Page : 27

37. Sinha N., Jain S., Tilekar A., Upadhayaya R.S., Kishore N., Jana G.H. and

Arora S.K.; Bioorg. Med. Chem Lett., 15, 1573, (2005).

38. Sriram D., Yogeeswari P. and Devakaram R.V.; Bioorg. Med. Chem., 14,

3113, (2006).

39. Terzioglu N. and Gursoy A.; Eur. J. Med. Chem., 38, 781, (2003).

40. Demirbas N., Karaoglu S., Demirbas A. and Sancak K.; Eur. J. Med. Chem.,

39, 793, (2004).

41. Gursoy E. and Guzeldemirci-Ulusoy N.; Eur. J. Med. Chem., 42, 320 (2007).

42. Bhandari S.V., Bothara K.G., Raut M.K., Patil A.A., Sarkate A.P. and Mokale

V.J.; Bioorg. Med. Chem., 16, 1822. a(2008).

43. Valentina P., Ilango K., Deepthi M., Harusha P., Pavani G., Sindhura K.L. and

Guru Keerthanan C.; J. Pharm. Sci. Res., 1, 74 (2009).

44. Bawa S. and Kumar S.; Ind. J. Chem., 48B, 142 (2009).

45. Kamel M.M., Ali H.I., Anwar M.M., Mohamed N.A. and Soliman A.M.; Eur.

J. Med. Chem., 45, 572. (2010).

46. Panneerselvam P., Priya G.M., Kumar N.R. and Saravanan G.; Ind. J.

Pharm.Sci., 71, 428 (2009).

47. Kamal, Vashi and Naik, H. B.; E-J Chem., 1(5), 272- 275 (2004).

48. Santosh, Kumar; Niranjan, M. S.; et al; J. Current Pharma. Res. 01, 39-42

(2010).

49. Hearn, Michael, J.; Cynamon, Michael H.; J. Antimicrobial Chemotherapy,

53, 185–191 (2004).

50. Chinnasamy, Rajaram Prakash; Sundararajan, Raja; Int. J. Pharmacy and

Pharma. Sci. 2(4), (2010).

51. Najim, A. Al-Masoudia; Nazik, M. Azizb; et al; Phosphorus, Sulfur, and

Silicon and the Related Elements, 184(11), 2891 – 2901 (2009).

52. Valentina, P.; Ilango, K.; et al; J. Pharm. Sci. & Res., 1(2), 74-77 (2009).

53. Sharma, M. C.; Sahu, N. K.; Kohalia, D. V.;et al; Digest J. Nanomaterials and

Biostruc. 4(1), 223 – 232 (2009).

54. Ha, Sie-Tiong; Ong, Lay-Khoon; Sivasothy, Yasodha; et al; American J.

Applied Sci. 7(2), 214-220, (2010).

55. Wadher, S. J.; Puranik, M. P.; et al; Int. J. Pharmtech Res., 1(1), 22-33,

(2009).

56. Naqvi, Arshi; Shahnawaaz, Mohd; Euro. J. Chem., 6(S1), S75-S78 (2009).


Page : 28

57. Guzeldemirci, Nuray Ulusoy; Ilhan, Eser; et al; Arch Pharm Res., 33(1), 17-

24, (2010).

58. Yang, Hai Jian; Sun, Wen Hua; et al; Chinese Chem. Let., 13(1), 3–6, (2002).

59. Yang, Zhaoqi; Sun, Pinhua; Molbank, M514 (2006).

60. Asiri, Abdullah, M. and Badahdah, Khadija O.; Molecules, 12, 1796-1804

(2007).

61. Lopez-Periago, A. M.; Garcia-Gonzalez, C. A.; at al; Chem. Commun., 46,

4315- 4317 (2010).


Page : 29

CHEMISTRY OF THIAZOLIDINONE: Thiazolidinone, which belong to an important group of heterocyclic

compounds have been extensively explored for their application in the field of

medicine. Thiazolidinone, in which a carbonyl group at position 2(I), 4(II) or 5(III)

have been subjected of extensive study in the recent past. Numerous reports have

appeared in the literature which highlight their chemistry and use.

S

NH

O S

NHO

S

NH

O

(I) (II) (III) 4-Thiazolidinones are derivatives of thiazolidinone with carbonyl group at 4-

position (II). Substituent in the 2, 3 and 5 positions may be varied, but the greatest

different in structure and properties is exerted by the groups attached to carbon atom

at the 2-position and two nitrogen atom at the 3-position. The cyclic structure was

assigned after recognisation of mercaptoacetic acid as a primary product of hydrolysis

of 3-phenyl-2-phenylimino-4-thiazolidinones.


A series of new 4-thiazolidinones were synthesized N'-(4-substituted-phenyl)-N"-1-[(3'-substituted phenyl)-6-tetrazolyl]-thiocarbamide(s) by Sawale, Archana [1].Which was further reacted with chloro acetic acid in presence of anhydrous sodium acetate and acetic acid to form new 4-thiazolidinone(s). The synthesized 4-thiazolidinones were screened against E. coli for their antibacterial activity. Some of the compound showed good antibacterial activity.

Prasad, Ashok; et.al [2] have prepared N-(2-aryl-4-oxothiazolidin-3-yl)-2-(5-(naphthalenyloxymethyl)-2-thioxo-1, 3, 4-oxadiazol-3(2H)-yl)acetamide. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities.

Yang, Yu-Shun; Zhang et.al [3] have performed the best in the thiazolidinone series (MIC values: 3.13-6.25 µg/mL). They also demonstrated strong broad-spectrum antimicrobial activity. Two compounds exhibited the most potent E. coli FabH inhibitory activity with IC50 of 4.6 and 8.4 µM. comparable with the pos. control DDCP (IC50 =2.8 µM). Docking simulation was performed to position compound [IV] and [V] into the E. coli Fab H structure active site to determine the probable binding model.


Page : 30

[IV] [V]

Chandramohan, S.; Elayaraja, R. et.al [4] have prepared three novel

substituted thiazolidin-4-one derivatives. The synthesized compounds showed good

antibacterial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas

aeruginosa and Salmonella typhi.

Gaikwad, Sajeevan et.al [5] have synthesized 5-(4-substituted-aryl)-7-

(naphtho[2, 1-b]furan-2-yl)-2H-thiazole[3, 2]pyrimidine-3(5H)-one derivatives. The

newly synthesized compounds were evaluated for their anti microbial activity.

Li, Xiaoliu; Chen, et.al [6] have prepared some thiazolidinone or

tetrahydrothiazinone fused aza sugar derivatives as anti-HIV agents. Compound [VI,

VII] showed inhibitory activity with IC50 of 4.49 µM against HIV reverse

transcriptase.

[VI] [VII]

[where in m = 1 or 2;n = 0-2; R = H, CH2OH, or CH2OTr;

P = H or hydroxy protective group]

Li, Xiaoliu et al.[7] have synthesized bi/ tricyclic azasugars fused thiazolidin-

4-one and thiazinan-4-one, by one-pot tandem Staudinger/aza-Wittig/cyclization

reaction under microwave radiation. The preliminary biological evaluation of

synthesized compounds were found to active the natural killer (NK) cells significantly

(immuno-potentiating activity) and exhibited weak inhibitory activity against

glucosidase. Yet none of these tested compounds [VIII] have obvious effects on T

cell proliferation.


Page : 31

[VIII]

A new series of N-[3-(10H-phenothiazin-10-yl) propyl]-2-aryl-4-oxo-5-

arylidene-3-thiazolidinecarboxamides [IX, X] were synthesized by Sharma, Ritu et

al.[8] All the compounds were screened for their antimicrobial activity against some

selected bacteria and fungi and for their anti tuberculosis activity,

[IX, X]

(R = CH Ar; Ar = Ph, 4-, 3- or 2-substituted

ClPh, BrPh, O2NPh, MeOPh, MePh, HOPh;)

4-thiazolidinonyl-quinazolin-4(3h)-ones of Diclofenac analog were designed

for a study of their biological Activity by Patel, Navin B.et.al.[9] Thiazolidinone

derivatives were screened in-vitro for their antimicrobial activity and several

compounds displayed good antibacterial as well as antifungal activity.

Rekha, S. et.al [10] have reported 5 - [[4 - (4 - methyl - 1 - piperazinyl)

phenyl] methylene] - 2, 4 - thiazolidinedione, 5 - [4 - (phenylamino)phenyl]

methylene] - 2, 4 - thiazolidinedione. The target compounds were screened for their

activity in a bovine serum denaturation (in vitro) assay (inflammation inhibitors).

They have reported all synthesized compounds were weakly active in the bovine

serum denaturation assay.

Alagawadi et.al [11] have designed new 2, 4-thiazolidinediones bearing

imidazo[2, 1-b][1, 3, 4] thiadiazole moiety. All the synthesized compounds were

evaluated for their preliminary in vitro antibacterial and antifungal activity and the

results revealed that most of the compounds showed high or moderate biological

activity against tested microorganisms.

Sharma, Nidhi et.al [12] have prepared 2-aryl-3-(benzimidazol-3-ylamino)-2-

methyl-4-thiazolidinones reported antibacterial and antifungal activity.


Page : 32

Maheta, S. et. al [13] have synthesized 4-chloro-2-hydroxy-N-(4-oxo-2-

arylthiazolidin-3-yl) benzamides. All the newly synthesized N-(oxo thiazolidinyl)

benzamides were evaluated for antibacterial and antifungal activities.

Murugan, V.et.al [14] have synthesized series of compounds [XI]. Among

synthesized compound they reported only three compounds have shown potent

antiulcer activity. Four compounds showed significant antibacterial activity. These

compounds were further subjected for antitubercular activity, and all of them showed

sensitivity at 50 and 100 µg/mL.

[XI].

[R =Ph, 4-MeOC6H4, 2-HOC6H, etc.].

Desai, N. C et.al [15] have synthesized several new 3-[2-(1Hbenzimidazol-2-

yl) phenyl]-2-arylthiazolidin-4-ones. All the synthesized compounds were evaluated

for antibacterial and antifungal activity against E. coli, S.aureus, P. aeruginosa, S.

pyogenes, C. albicans, A. niger, and A. clavatus.

Tomasic et.al [16] reported 2-thioxothiazolidin-4-one, thiazolidine-2, 4-dione,

2-iminothiazolidin-4-one or imidazolidine-2, 4-dione ring connected by a benzylidene

group. These compounds were designed to target the D-Glu- and the diphosphate-

binding pockets of the MurD active site and were evaluated for inhibition of MurD

ligase from Escherichia coli. The most potent compounds [XII] (R)- and (S)-I

inhibited MurD and the specific binding mode of (R)-I in MurD active site was

established by high-resolution NMR spectroscopy.

[XII]

Recently, some PPAR-γ agonists like pioglitazone, rosiglitazone, and other

newer thiazolidine-2, 4-dione (TZD) derivatives.

Raghubir et.al [17] have synthesized, thiazolidin-4-one derivatives and bio

evaluated in focal cerebral ischemia model in rats with an aim to ameliorate cerebral

ischemic damage. They have suggested that some of the synthesized thiazolidin-4-one

substituted PPARγ agonists exhibit better neuro protection and have potential to


Page : 33

ameliorate the ischemic damage. Therefore, this novel class of compounds could be

further suitably modified to obtain potent anti-ischemic agents, warranting clinical

exploitation.

Some new 3-[(1, 2, 4-triazolo[3, 4-b]-1, 3, 4-thiadiazol-2-yl)phenyl]-2-

arylthiazolidine-4-ones [XIII] have prepared by Parmar, Kokila et.al.[18] The

compdounds have been evaluated for antibacterial activity against B. subtilis, S.

aureus, P.aeruginosa and E. coli.

[XIII]

Ar = Ph, 4-MeOC6H5, 2-HOC6H5, etc.

Thomas, Asha B et.al [19] have synthesized N-(2-aryl-4-oxo-3-thiazolidinyl)

isonicotinamide by a novel method of stirring and sonication. Results indicate that

high yields and shorter reaction times can be achieved by employing this novel green

route method.

Several (phenylmethylene) thiazolidinedione derivatives were prepared by

Venkatesan, S .et.al [20]. The acute toxicity of these compounds were assayed by

determine of their LD50 and all compounds were interestingly less toxic than the

reference drug (diclofenac). The title compounds were evaluated in carrageenan-

induced rat paw edema model and it was discovered that they displayed activity as

inflammation inhibitors.

5-(phenylmethylene)-2-thioxo-4-thiazolidinone, (benzylidene)rhodanine

derivatives were prepared by Opletalova, et.al.[21].The title compounds were

evaluated for their lipophilicity RP-HPLC analysis and these compounds were

evaluated for their ability to inhibit photosynthetic electron transport (PET) in spinach

(Spinacia oleracea L.) chloroplasts and their ability to reduce the chlorophyll content

in freshwater algae (Chlorella vulgaris). They found that majority of the tested

compounds showed the lipophilicity of the compound and electronic properties of the

substituent were not decisive for PET-inhibiting activity. The most potent PET

inhibitor was (5Z)-5-(4-bromobenzylidene)-2-thioxo-4-thiazolidinone (IC50 = 3.0

μmol/L) and the highest algicide activity was displayed by (5Z)-5-(4-

chlorobenzylidene)-2-thioxo-4-thiazolidinone (IC50 = 2.2 μmol/L).


Page : 34

A series of novel 4-thiazolidinone and indolin-2-one hybrid derivatives have

been designed and synthesized and their cytotoxic activities were evaluated in vitro

against three human cancer cell lines including HT-29 (human colon cancer), H460

(human lung cancer), MDA-MB-231 (human breast cancer) by MTT assay by Wang,

Shuobing et.al.[22]. Several potent target compounds were further evaluated against

one cancer cell line SMMC-7721(human liver cancer) and one normal cell line WI-38

(human fetal lung fibroblasts). Most of the prepared compounds exhibited significant

antitumor activities against different human cancer cell lines. Compound [XIV] (IC50

= 0.025 μM,, 0.075 μM,, 0.77 μM,, 1.95 μM, ) was 52, 36, 4.8 and 3.3 times more

active than Sunitinib (IC50 = 2.2 μM,, 2.7 μM,, 3.7 μM,, 6.47 μM, )against HT-29,

H460, MDA-MB-231 and SMMC-7721 cancer cell line, respectively.

[XIV]

N-(4-oxo-2-phenylthiazolidin-3-yl)-1-(2-oxo-2H-benzopyran-6-yl)-5-

hydroxy-2-methylindole-3-carboxamides were prepared by Mulwad, et.al.[23] All the

compounds were screened for their antimicrobial activity and exhibited antibacterial

and antifungal activity.

N(1)-[(5-arylidenamino-1, 3, 4-thiadiazol-2-yl)methyl]- and N(1)-{[2-(2-aryl-

5-methyl-4-oxothiazolidin-3-yl)-1, 3, 4-thiadiazol-2-yl]methyl}-2-

methylbenzimidazoles were prepared by Srivastava, S. K et. al. [24].The newly

synthesized compounds were studied for antimicrobial activity against B. subtilis, E.

coli, K.pneumoniae, and S. aureus bacteria and A. niger, A. flavus, F. oxysporum and

T. viride fungi in vitro at 50 and 100 ppm concentrations. Some of the compounds

displayed pronounced biological activity.

(fluorenylidene) (oxo) - α-[(phenyl) hydrazinylidene] thiazoleacetonitrile and

(indenylidene) (oxo) - α-[(phenyl) hydrazinylidene] thiazoleacetonitrile derivatives

were synthesized and evaluated in-vitro against Gram-positive bacteria and Gram-

negative bacterial (Staphylococcus aureus, Escherichia coli) and zoo pathogenic fungi

(Candida albicans, Aspergillus flavus) by Metwally, Nadia Hanafy et.al [25] and it

was discovered that they displayed activity as antibacterial agents.


Page : 35

A series of 3-[4-(6-bromo-2-oxo-2H-chromen-3-yl)-1, 3-thiazol-2-yl]-2-

(substituted phenyl) 1, 3-thiazolidin-4-ones were synthesized by Joshi, Aakanksha

et.al.[26] The synthesized compounds were evaluated for their anti- antibacterial and

in vitro antioxidant activity.

3-[[(5-Bromo-2-hydroxyphenyl)methylene]amino]-2-thioxo-4-thiazolidinone

derivatives were synthesized by Abd. El Fattah et.al.[27].The title compounds were

evaluated against Pseudomonas sp., Escherichia coli, Bacillus subtilis,

Staphylococcus aureus, Candida albicans and it was discovered that they displayed

antibacterial activity, but not antifungal activity.

A series of 5-arylmethylidene-1, 3-thiazolidine-2, 4-diones, and 3-(7-hydroxy-

2-oxo-2H-chromen-4-ylmethyl)-5-arylidene-1, 3-thiazolidine-2, 4-diones, e.g., [XV,

XVI]. The synthesized compounds, 5-arylmethylidene-1, 3-thiazolidine-2, 4-diones

and 3-(7-hydroxy-2-oxo-2H-chromen-4-ylmethyl)-5-arylidene-1, 3-thiazolidine-2, 4-

diones, were evaluated by Cacic, Milan et.al [28] for their antioxidant activity.

[XV] [XVI].

Srikanth, L. et.al [29] have synthesized 5-[4-[7-[(1E)-3-oxo-3-phenyl-1-

propenyl]-8-quinolinyl] phenoxy]-2, 4-thiazolidinedione for a study of their anti

diabetic activity. The synthesized compounds were screened against a rat model and it

was discovered that these compounds displayed activity as oral hypoglycemic agents

in comparison with Rosiglitazone.

3-imino-2-thioxo-4, 5-dihydro-4-thiazolidinone were designed and

synthesized by Makki, Mohammad S.et.al.[30]. The title compounds were evaluated

against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Pseudomonas

vulgaris and Shigella flexneri and they reported that these compounds displayed

antimicrobial activity.

Tirlapur, Vijay Kumar; et.al [31] have prepared thiazolidin-4-ones and

pyrimidines incorporating benzo[b]thiophene. The synthesized compounds were

screened for antibacterial, antifungal, and anti inflammatory activity.

A series of thiazolidinones were prepared by Patel, Navin B et.al.[32] The in

vitro antimicrobial screening of the compounds were carried out against two Gram


Page : 36

positive (S. aureus, S. pyogenes), two Gram negative(E. coli, P. aeruginosa) bacteria

and three fungalspecies (C. albicans, A. niger, A. clavatus) using the broth micro

dilution method. Some of the compounds [XVII] were found to be comparable with

standard drugs.

[XVII]

Meshram, Jyotsna; et.al [33] have used Zeolite 5Å as an efficient and cost

effective catalyst for the synthesis of bis-thiazolidinones [XVIII]. Starting from bis-

imines [XIX] and mercaptoacetic acid. The drug-like properties of the products were

evaluated using Molinspiration bio informatic software and discussed.

[XVIII] [XIX]

R = Ph, 2-HOC6H4, 3-O2NC6H4, 4-MeOC6H4,

A series of nine new 5-{[3-(aryl)-1-phenyl-1H-pyrazol-4-yl] methylene}-3-

phenylthiazolidine-2, 4-diones was synthesized by Prakash, et.al.[34] All the

compounds were screened for their in vitro antibacterial (Staphylococcus aureus,

Bacillus subtilis, Pseudomonas aeruginosa and Escherichia coli) and antifungal

(Aspergillus niger and A. flavus) activity. Biological activities of these compounds

were compared with those of common available antibiotics, ciprofloxacin and

antifungal agent fluconazole. Out of the nine compounds tested for anti fungalactivity,

five showed > 50% inhibition against the A. flavus and three compounds showed >

50% inhibition against A. niger.

Singh, Arun; et.al [35] have synthesized 3-(2-(5-benzoyl-1H-

benzo[d]imidazol-1-yl) acetyl)-5-benzylidene-2-alkylthiazolidin-4-ones. All the

newly synthesized compounds were evaluated for their antibacterial and antifungal

activities.

Vandana, Tiwari; et.al [36] have used Zeolite 5A as an efficient and cost-

effective catalyst for the prepn. of 2-(2-chloro-3-quinolinyl)-3-phenyl-4-


Page : 37

thiazolidinone derivatives. The title compounds were evaluated for their antibacterial

activity against Staphylococcus aureus, Pseudomonas vulgaris, Pseudomonas

aeruginosa and Escherichia coli and it was discovered that several compounds

possessed broad-spectrum antibacterial activity.

Sharma, M. C.et.al [37] have prepared 2-(2-substituted-phenyl)-3-(4-{1-[2-

(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl])-1H-benzoimidazol-2-yl}-phenyl)-

thiazolidin-4-ones. All the synthesized compounds were screened for Angiotensin (A

II) Receptor Antagonist antihypertensive activity with biphenyl tetrazole schiff bases

thiazoldine-4-one showed good activity compared with losartan.

Indolin-2-on-3-spirothiazolidinones, e.g. [XX], were identified by Vintonyak,

Viktor V et.al.[38] as a novel class of potent and selective substrate-competitive

inhibitors of Mycobacterium tuberculosis protein tyrosine phospgatase B (MptpB).

[XX]

Patel, Hasmukh S.; et.al [39] have synthesized 2-hydroxy-N-(4-oxo-2-

arylthiazolidin-3-yl) benzamides. All the newly synthesized compounds were

evaluated for their antibacterial and antifungal activities.

Novel thiopyrano[2, 3-d]thiazoles [XXI a, b, c, d] were synthesized by

Zelisko, N. I.; et.al [40]. Preliminary evaluation of anticancer activity of some

products was carried out.

[XXIa, b, c, d]

Aly, Ashraf A.; et.al [41] have prepared (Z)-methyl-2-arylhydrazide-4-oxo-3-

(propan-2-ylideneamino) thiazolidine-5-ylidene-acetates. Antitumor activity of


Page : 38

selected compounds was evaluated in hepatocellular carcinoma cells with compound

[XXII] demonstrating the highest degree of cell proliferation inhibition. Compound

[XXII] also demonstrated the greatest antioxidant activity based on results from the

DPPH radical scavenging assay.

[XXII]

A new series of 2-aryl-N-(4-phenylthiazolyl)-4-thiazolidinones were prepared

by Prabhu, Padmavathi P et.al [42]. The products were evaluated for in-vitro growth

inhibiting activity against several microbes. Some of the compounds showed

anthelmintic activity.

5-chloro-3-methyl-2-(2'-aminothiazole-4'-yl)benzofuran incorporate schiff's

base, thiazolidinone derivatives [XXIII] were synthesized by Basawaraj, Raga

et.al.[43]. The synthesized compounds were screened for antimicrobial and some

selected compounds were screened for their antitubercular activity.

[XXIII]

A series of 2-aryl, 3-benzyl-(1, 3-oxazolidine or 1, 3-thiazolidine)-4-ones,

possessing a methyl sulfonyl pharmacophore were synthesized by Zarghi, A.; et. al.

[44]. They evaluated their biological activities as selective cyclooxygenase-2 (COX-

2) inhibitors. Compound [XXIV] was identified as the most potent (IC50 =0.21 μM)

and selective (S. I. > 476) COX-2 inhibitor among the synthesized compoundsIt also

was a more selective COX-2 inhibitor than the parent reference compound celecoxib

(S. I. > 403).


Page : 39

[XXIV]

Verkman, Alan S. et al [45] have provides methods for identifying compounds

that are inhibitors of a calcium-activated chloride channel. Aminothiophene and

aminothiazole compounds [XXV] comprising these compounds are described that

inhibit efflux of chloride through a calcium-activated chloride channel and are useful

for treating diseases, disorders, and sequelae of diseases, disorders, and conditions

that are associated with aberrantly increased chloride and fluid secretion, e.g.

secretary diarrhea.

[XXV]

A range of benzothiazoles [XXVI], [XXVII] and [XXVIII] were synthesized

by Sonwane, S. K et.al [46]. The synthesized compounds were screened in vitro for

their antimicrobial activity against Bacillus subtilis, Escherichia coli, Klebsiella

pneumoniae and Streptococcus aureus bacteria and Aspergillus niger, Aspergillus

flavus, Fusarium oxisporum and Trichoderma viridefungi respectely. Some of the

compounds displayed pronounced biological activity.

[XXVI], [XXVII] and [XXVIII]

(R1 = 2-Cl, 3-Br, 4-MeO, 2-NO2, 4- N Me2, etc.)


Page : 40

REACTION MECHANISM:

..

R'

N

H

R

HOOC SH

..

.. HOOC

-

NH

R'H

R

S

O

O+

H HN H

R'H

R

S

O+

N

R'H

R

S

O

.. ..

N R'

H

R

S+ H

H+ Shift

-H2O

Protonation

-H+


Page : 41

References : 1. Sawale, Archana A.; Bendre, Ratnmala S.; Patil, Pradip R.; Res. J. of Pharm.,

Bio. Chem. Sci., 3(3), 415-420. (2012).

2. Prasad, Ashok; Nimavat, K. S.; Vyas, K. B: J. Chem. Pharm. Res. 4(6), 2959-

2963 (2012).

3. Yang, Yu-Shun; Zhang, Fei; Gao, Chao; Zhang, Yan-Bin; Wang, Xiao-Liang;

Tang, Jian-Feng; Sun, Jian; Gong, Hai-Bin; Zhu, Hai-Liang; Bioorg. Med.

Chem. Lett., 22(14), 4619-4624. (2012).

4. Chandramohan, S.; Elayaraja, R.; Thiripura Salini, S.; Elavarasan, A.; Senthil

Kumar, R.; International J. Pharm. Sci. and Res., 3(5), 1516-1519 (2012).

5. Gaikwad, Sajeevan; Suryawanshi, Venkat; Vijapure, Yogiraj; Shinde, Vishnu;

J. Chem. Pharm. Res., 4(3), 1851-1855 (2012).

6. Li, Xiaoliu; Chen, Hua; Zhang, Hongzhi; Qin, Zhanbin; Zhang, Pingzhu; Yin,

Qingmei; Zhang, Jinchao ; Faming Zhuanli Shenqing, CN 102417515 A

20120418 (2012).

7. Li, Xiaoliu; Qin, Zhanbin; Yang, Tianyu; Zhang, Hongzhi; Wei, Sinan; Li,

Chunxiao; Chen, Hua; Meng, Ming; Bioorg. Med. Chem. Lett., 22(8), 2712-

2716 (2012).

8. Sharma, Ritu; Samadhiya, Pushkal; Srivastava, Savitri D.; Srivastava, Santosh

K ; J. of the Serbian Chem. Soc., 77(1), 17-26 (2012).

9. Patel, Navin B.; Patel, Jaymin C.; Patel, Virendra N.; Latin Ame. J. Pharmacy,

30(7), 1274-1282 (2011).

10. Rekha, S.; Shantharam, U.; Chandy, Vineet ; International Res. J. Pharmacy

2(9), 81-84 (2011).

11. Alagawadi, Kallanagouda R.; Alegaon, Shankar G; Arabian J. Chem. 4(4),

465-472 (2011).

12. Sharma, Nidhi; Pathak, Devender; Indian J. of Hetero. Chem., 21(1), 29-32

(2011).

13. Maheta, S.; Patel, S. J.; Bulgarian Chem. Communications, 43(3), 411-418

(2011).


Page : 42

14. Murugan, V.; Shukla, Manisha; Geetha, K. M.; Ashwini, A. K.; Singh, Vishal;

Pharma Chemica, 3(4), 509-516 (2011).

15. Desai, N. C.; Bhatt, Nayan; Kumar, Mukesh; Makwana, Atul ; Indian J.

Chem., Section B: Organic Chem. Including Med. Chem., 50B(7), 941-945

(2011).

16. Tomasic, Tihomir; Kovac, Andreja; Simcic, Mihael; Blanot, Didier;

Grdadolnik, Simona Golic; Gobec, Stanislav;Kikelj, Danijel; Peterlin Masic,

Lucija; Eur. J. Med. Chem., 46(9), 3964-3975 (2011).

17. Raghubir, Ram; Verma, Rajkumar; Samuel, Sheeba S.; Raza, Saman; Haq,

Wajahul; Katti, Seturam B.; Chem. Biology & Drug Design, 78(3), 445-453

(2011).

18. Parmar, Kokila; Prajapati, Sarju; Patel, Rinku; Patel, Rekha; Res. J. Chem.

Sci., 1(1), 18-24 (2011).

19. Thomas, Asha B.; Sharma, Piyoosh A.; Tupe, Preeti N.; Badhe, Ravindra V.;

Nanda, Rabindra K.; Kothapalli, LataP.; Paradkar, Omkar D.; Banerjee,

Anupam G.; Deshpande, Avinash D.; Green Chem. Lett. and Reviews, 4(3),

211-217 (2011).

20. Venkatesan, S.; Singh, Rameshwar; International J. Chem. and Pharm. Sci.,

1(2), 17-23 (2010).

21. Opletalova, Veronika; Dolezel, Jan; Kralova, Katarina; Pesko, Matus; Kunes,

Jiri; Jampilek, Josef; Molecules, 16, 5207-5227 (2011).

22. Wang, Shuobing; Zhao, Yanfang; Zhang, Guogang; Lv, Yingxiang; Zhang,

Ning; Gong, Ping ; Eur. J. Med. Chem., 46(8), 3509-3518 (2011).

23. Mulwad, Vinata V.; Parmar, Hitesh T.; Mir, Abid A.; Acta Poloniae

Pharmaceutica, 68(1), 49-55 (2011).

24. Srivastava, S. K.; Sonwane, S. K.; Verma, Smita ; International J. Pharm. Sci.

(Bangalore, India), 2(3), 656-663 (2010).

25. Metwally, Nadia Hanafy; El-Taher, Sabry; Hetero., 83(5), 1029-1040 (2011).


Page : 43

26. Joshi, Aakanksha; Narayanaswamy, Venugopala Katharigatta; Rao, Gopal

Krishna; Devi, Kalpana; Pathak, Arun ; Indian J. of Heter. Chem., 20(3), 295-

296 (2011).

27. Abd El Fattah, M. E.; Soliman, A. H.; Abd Allah, H. H.; Seijas, Julio A.;

Vazquez Tato, M. Pilar ; International Electronic Conference on Synthetic

Organic Chem., 14th, Nov. 1-30, 2010 abdel4/1-abdel4/5. (2010).

28. Cacic, Milan; Molnar, Maja ; Zeitschrift fuer Naturforschung, B: A J. of

Chem. Sci. 66(2), 177-183 (2011).

29. Srikanth, L.; Raghunandan, N.; Srinivas, P.; Amarender Reddy, G;

International J. of Pharma and Bio Sci., 1(4), 120-131 (2010).

30. Makki, Mohammad S. T.; Abdel-Rahman, Reda M.; El-Shahawi, Mohammad

S; International J. of Chem. (Toronto, ON, Canada), 3(1), 181-192 (2011).

31. Tirlapur, Vijay Kumar; Dhawan, Aditya ; Indian J. Heter. Chem., 20(2), 141-

144 (2010).

32. Patel, Navin B.; Shaikh, Faiyazalam M.; Scientia Pharma., 78(4), 753-765

(2010).

33. Meshram, Jyotsna; Ali, Parvez; Tiwari, Vandana ; Green Chem. Lett. and

Reviews, 3(3), 195-200 (2010).

34. Prakash, Om; Aneja, Deepak Kumar; Arora, Sanjiv; Sharma, Chetan; Aneja,

K. R. ; Med. Chem. Res., 21(1), 10-15 (2012).

35. Singh, Arun; Kumar, Deepak; Bux, F. B.; Pharmacia Lettre, 2(3), 276-285

(2010).

36. Vandana, Tiwari; Jyostna, Meshram; Parvez, Ali ; Pharma Chemica, 2(3),

187-195 (2010).

37. Sharma, M. C.; Kohli, D. V.; Sharma, Smita; Sharma, A. D; Chemica Sinica,

1(1), 73-85 (2010).

38. Vintonyak, Viktor V.; Warburg, Karin; Kruse, Holger; Grimme, Stefan;

Huebel, Katja; Rauh, Daniel; Waldmann, Herbert: Angewandte Chemie,

International Edition, 49(34), 5902-5905 (2010).


Page : 44

39. Patel, Hasmukh S.; Patel, Sumeet J.; Phosphorus, Sulfur and Silicon and the

Related Elements, 185(8), 1632-1639 (2010).

40. Zelisko, N. I.; Atamanyuk, D. V.; Lesik, R. B.; Zhurnal Organichnoi ta

Farmatsevtichnoi Khimii, 8(2), 69-73 (2010).

41. Aly, Ashraf A.; Brown, Alan B.; Abdel-Aziz, Mohamed; Abuo-Rahma,

Gamal El-Din A. A.; Radwan, Mohamed F.;Ramadan, Mohamed; Gamal-

Eldeen, Amira M.; J. of Heter. Chem., 47(3), 547-554 (2010).

42. Prabhu, Padmavathi P.; Satyanarayana, D.; Shastry, C. S.; International J. of

Chem. Sci., 7(4), 2583-2590 (2009).

43. Basawaraj, Raga; Patil, Srikanth; Patil, Ashok; Vijaykumar, T.;

Parmeshwarappa, G. From Organic Chem.: An Indian J., 5(1), 68-72 (2009).

44. Zarghi, A.; Arefi, H.; Dadrass, O. G.; Torabi, S. From Med. Chem. Res., 19(8),

782-793 (2010).

45. Verkman, Alan S.; De La Fuente Gonzalez, Ricardo: PCT Int. Appl., WO

2009079373 A2 20090625 (2009).

46. Sonwane, S. K.; Srivastava, S. D.; Srivastava, S. K.: J. of Indian Council of

Chemists, 25(1), 15-18 (2008).


Page : 45

CHEMISTRY OF AZATIDINONE:

The azetidinone or β-lactums have been known as products of the reaction of

certain ketenes with anils. The discovery, during world war-II, that the important

antibiotics known as the penicillin contained a fused ring systems of which one part

was a β-lactums ring.

The systematic name assigned to the conjugated doubly unsaturated ring made

up of three carbon atoms and one nitrogen atom is azete [1], accordingly, the dihydro

derivatives is named azetine and the saturated ring system is name azetidine.

N NN

N

O1-azetine azetidine 2-azetidinoneazete

The 2-carbonyl derivative of azetidine is known as 2-azetidinones. The

development of the chemistry of the β-lactms was initiated by Staudinger and his co-

worker during his classical studies of ketenes [2]. For several years these researches

stood as only important contribution to this field of heterocyclic chemistry. However,

since 1940 a tremendous impetus has been given to the reactivity of these compounds

because of their relation to the structure of the naturally occurring penicillin.

S

O

NHO

RCH3

CH3

O

OH

General Structure of penicillin

A review of the earlier literature by Mogilaiah K. et al [3] describes the

synthetic procedure for 2-azetidenones. Various methods for the preparation of 2-

azetidinones have been described [4-6].

The four member 2-azetidinone rings appears to be smallest cyclic system that

is of accommodating the amide function as a consistent which is also known as β-

lactum ring.


Page : 46

BIOLOGICAL SIGNIFICANCE: Over the years it has been of great practical significance because of their good

pharmacological and biological activities such as antidepressants, antidegenerative,

sedative [7], Fungicidal [8], anti-inflammatory [9], antibacterial[10-13].

A novel, practical and stereo selective synthesis of (3R, 4R)-4-acetoxy-3-

[(R)-1-(t-butyldimethyl silyloxy) ethyl] -2-azetidinone, a key intermediate in the

prepn. of β-lactum antibiotics is reported by Grzeszczyk, Barbara; et.al. [14]

Mccomas, Casey Cameron; et.al [15] have prepared 2-azetidinone

derivativesand their pharmaceutically acceptable salts, are prepd. and disclosed as

antiviral agents. Some compounds were evaluated in HCV replicon inhibition assays

Gomathy, S.; Gowramma, B et.al [16] have synthesized naphthalene bearing 2-

azetidinone derivatives. The synthesized compounds are evaluated for their

antiparkinson's activity by 6-Hydroxydopamine lesioned rat's model (6-OHDA).

Among evaluated 2-azetidinone derivatives, compound with nitro Ph group at 2nd

position exhibited max. anti parkinson's activity.

4-aryl-3-chloro-1-(thieno [2, 3-d] pyrimidin-4-ylamino)azetidin-2-ones were

synthesized by Akbari, Vikunjana K et.al [17]. The final compounds were screened

for antibacterial activity against from Gram positive and Gram negative bacteria as

well as for antifungal activity.

Antre, R. V.; et.al [18] have described development of new chemical entities

of Edaravone (3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) for their antibacterial

activity. Various N-(substituted benzylidenyl)-[2-(4, 5-dihydro-3-methyl-5-oxo-1-

phenyl-1H-pyrazol-4-yl)acetohydrazide] and 2-(4, 5-dihydro-3-methyl-5-oxo-1-

phenyl-1H-pyrazol-4-yl)-acetamide- (3-chloro-4-substituted phenylazetidin-2-one)

(DTa-DTe) screened for their antibacterial activity against Escherichia coli and

Bacillus subtilis.

A series of [1-(2-aryl-5-mercapto-1, 2, 4-triazol-1-yl)-3-(2-chlorophenoxy) -4-

(3-indolyl)] azetidin-2-ones were synthesized for anticonvulsant activity by Garg,

Neha;et.al. [19.] All compounds were screened in vivo for their anticonvulsant

activity and acute toxicity studies.

An efficient and extremely fast procedure for the synthesis of 3-chloro-4-[4-

(diethyl amino)-2-hydroxyphenyl] -N-phenyl-2-azetidinone derivatives were reported

by Raval, Jignesh P et.al. [20] under microwave irradiations. All synthesized target


Page : 47

compounds were screened for their antifungal activity and their antibacterial activity

against various Gram-positive and Gram-negative bacteria (Bacillus subtilis,

Staphylococcus aureus, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa,

Candida albicans, Aspergillus niger.

A series of 2-azetidinones and 4-thiazolidinones of 4, 4’-sulfonyldianiline, e.

g. [I and II] have been synthesized under microwave irradiation and conventional

heating by Bhusnure et.al. [21].All the synthesized products were screened for their in

vitro antibacterial, antifungal and anti-tubercular activity. The results indicated that

the synthesized compounds have moderate to potent activities.

[I]

[II]

Several 2-aminomethylene-[2-(3-chloro-2-oxo-4-aryl-1-azetidinyl)-1, 3, 4-

thiadiazol-5-yl] pyridine derivatives, 2-aminomethylene-[2-(2-aryl-4-thiazolidinyl)-1,

3, 4-thiadiazol-5-yl] pyridine derivatives were designed by Rajput et.al. [22] for a

study of their biological activity. They evaluated for their activity as antifungal agents

and they discovered that one compound displayed activity greater than Fluconazole

and Griseofulvin.

Smith Elizabeth M et. al [23] have prepared series of spiro-azetidines and

azetidinones and evaluated as novel blockers of the T-type calcium channel

(Ca(V)3.2) which is a new therapeutic target for the potential treatment of both

inflammatory and neuropathic pain.

Sayyed, M. A.; et.al [24] have synthesized 2-azetidinones were screened for

their antibacterial activity against E. coli, S. aureus, X. citri and E. carotovora. Some

of the compounds showed better activity than slandered antibiotic Tetracycline.

3-chloro 4-Aryl N-Pyridine 2-yl 2-Azetidinone derivatives were prepared by

Ramalakshmishmi, Natarajan et.al . [25]. All the compounds were subjected to

leptospirocidal study. Among the synthesized compounds some showed significant


Page : 48

activity and the compounds few showed moderate activity. From the above summary

they reported that forming azetidinone nucleus at the side chain of 2-amino pyridine

showed significant leptospirocidal activity.

Bhusare S. R. et al have synthesized [26] 2-azetidinones having structure [III].

All the synthesized compounds are screened for their antimicrobial activity.

S

NOCH3

N

O

Cl

CH3

Cl

I

BrN

N

N

N

SH

N

ClOR

[III] [IV]

Priyadarsani, Vijyaraj, Ravi T. K. and Prabha [27] have synthesized some

azetidinones [IV] for their antitubecular, antibacterial, antifungal activities.

Z. Huibin et al [28] have synthesis of a series 2-azetidinones with ester or amide

group in C-3 side chain. Their cholesterol absorption inhibition activity was assessed

in orally dosed, cholesterol fed hamsters. It was demonstrated that compound with

amide group in C-3 side chain exhibited high cholesterol absorption inhibition

activity.

Padam Kant and Saxena R. K. [29] synthesized 2-azetidinone derivatives [V, VI]

containing quinazoline scaffold as an antibacterial and antifungal agents.

N

N

O

C6H5

N

HC

CH3

NO

OO

N

NN

S

NN

N

O

Ar

H

ClR

Ar = 3-OCH3-C6H5,2-Cl-C6H5

[V] [VI]

Azetidiones [VII a, b] and thiazolidinones II (R1-R3 as above) were

synthesized by Shanmugapandiyan et.al. [30]. The synthesized compounds were

screened for antibacterial (Bacillus cereus, Escherichia coli, Micrococcus luteus,

Klebssiela pneumoniae, Staphylococcus aureus and Salmonella epidermidis),

antifungal (Aspergillus niger and Candida albicans), analgesic activity by writhing

reflex method and anti-inflammatory activity by carrageen an induced paw edema

method. The synthesized compounds showed significant activity of antibacterial,

antifungal, analgesic and anti-inflammatory activity comparable to that of standard.


Page : 49

[VII a, b] R1, R3 = H, OMe; R2 = H, Cl, OH, Me, NMe2, OMe

Triazoles [VIII a, b] which were prepared by Deeb, A.;et.al, [31] showed that

they are potential bactericides.

[VIII a, b]

(R1 = H, Cl, OMe, NMe2, NO2; R2 = Cl, phthalimido)

Abdel-Rahman, A. E et.al.[32] have synthesized [IX a, b, c] for bactericidal

activity. Thus, II (R = H, R1 = OMe) and III (R = H, R1 =Cl, NMe2, R2 = Cl) are

effective against Salmonella and III (R = H, R1 = NMe2, R2 = phthalimido) against

Proteus.

[IX a, b, c]

The azetidinones [X] were obtained by Abdel-Rahman, A. E et.al. [33] have

showed variable bactericidal activity.

[X]


Page : 50

S. K. Srivastava [34] have synthesized several 1-[5’-N’-1, 2, 4-

triazolomethyl)-1’, 3’, 4’-thiadiazole-2’-yl] -4-(substituted phenyl)-3-chloro-2-

oxaazetidines [XI] and evaluated for their antibacterial, antifungal, anticonvulsant and

anti-inflammatory activities.

O

N

S

R2

N

R1

NH

O

ClO

Where R1= H, CH3; R2= H,Br,OH

[XI]

N. R. Pai and J. P. Suryavanshi [35] have synthesized N-{naphtha-[1, 2-b] -

pyrano-[3, 4-d] -thiazol-8-yl} spirondoloazetidin-2-one and evaluated for their

antibacterial activities.

Various 4 – aryl – 1 - (aryl amino benzothiazolyl carbamoylphenyl) – 3 -

chloroazetidin-2-ones have been synthesized by Kumar, M. M. et.al. [36]. The

compounds were tested for anti-inflammatory activity (in-vitro) by protein

denaturation method and showed significant activity at low and high concentration

compared to standard drugs.

A novel series of new isonicotinyl hydrazide derivatives containing 2-

azetidinone nucleus were synthesized by Jaju, Sandip; Palkar et.al. [37]. All the

synthesized compounds were tested for their in-vitro anti mycobacterial activity

against Mycobacterium tuberculosis H37Rv using Alamar-Blue susceptibility test,

and the activity is expressed as the min. inhibitory concn. (MIC) in μg/mL. Among

the series, few compounds displayed an encouraging anti mycobacterial activity

profile as compared to that of the reference drugs isoniazid / rifampicin.

Galletti, Paola et.al [38] have described the synthesis and biological evaluation

of a series of novel β-lactums. In vitro inhibition assays against HDAC isoforms

showed an interesting isoform-selectivity of these compounds towards HDAC6 and

HDAC8. The isoform selectivity changed in response to modification of the

azetidinone-ring nitrogen atom substituent. The presence of an N-thiomethyl group is

a prerequisite for the activity of these compounds in the micromolar range towards

HDAC8.

A five and six membered heterocyclic systems containing nitrogen, oxygen

and sulfur of fused β-lactums incorporating thienopyridazine [XII] were found to

possess interesting biological properties were successfully synthesized by Solieman


Page : 51

H. A, Abd El. Latif F. M Khalil M. A. and Elazab I. H [39] thereby enhancing the

activity of β-lactum ring systems.

NN

SO

H5C2O

Ph

O

NHCO NAr

OCl

[XII]

P. S. Reddy and co workers [40] have synthesized novel bisquinazoline β-

lactum derivatives [XIII] having following structure.

N

N

O

CH3

N Z N

N

O

CH3

N

O O [XIII]

Moreover, 2-Azetidinone derivatives have been reported to possess Anti-

HCMV activity, [41]. Antiviral activity [42] and cholesterol absorption inhibition

activity [43].

3-Benzylazetidine-2-one derivatives were designed and evaluated as a novel

series of chymase inhibitors by Aoyama Y et.al [44]. Structure-activity relationship

studies of 3-benzylazetidine-2-ones, which exhibited 3.1 nM inhibition of human

chymase and enhancement of stability in human plasma (t(1/2) 6h).

The design and synthesis of a biotin-tagged photo reactive analogue C-4 of the

cholesterol absorption inhibitor Ezetimibe is described by Frick Wendelin et.al. [45].

Photo affinity labeling of intestinal brush border membrane vesicles with C-4 and

subsequent streptavidin-biotin chromatography leads to selective extraction of a 145

kDa integral membrane protein as the molecular target for cholesterol absorption

inhibitors.

Hassan, Khairy M et al [46] have synthesized new sulfa drugs [XIV, XV] (R=

aryl and R1 = heterocycle) contg. both β--lactum moieties is described. Biological.

screening of these compounds on some strains of pathogenic bacteria indicated they

have a different mechanism of action from that already known for the sulfa drugs.

[XIV, XV]


Page : 52

REACTION MECHANISM:

R

R'

N

H

R

..

N R'HR

O

Cl Cl

O+

H3CH2C

N CH2CH3

H3CH2C

H3CH2C

N+

CH2CH3

H3CH2C

Cl Cl

O-

ClO +

Chloro acetyl chloride

Step‐1

Step‐2

ClO O

-

Cl

R'

N+

HR

Ketene

(C2H5)3 N+.HCl

-


Page : 53

References: 1. Patterson and Cappel; The Ring Index, Reinhold Publishing Corp., N.Y., P4

(1940).

2. Staundinger, K. Die; Enke, Stattgart (1912).

3. Mogilaiah, K., Reddy, P. R. and Rao, R. B.; Ind. J. Chem., 38B, 495, (1999).

4. Pandey, V. K., Gupta, V. D., Upadhay, M. and Singh, V. K.; Ind. J. Chem.,

44B, 158, (2005).

5. Sheehan, J. C., Bose, A. K.; J. Ame. Chem. Soc., 73, 1761, (1951), 72, 5158,

(1950).

6. Chatterjee, B. G. C., Rao, V. V., Mazumdar, B. N. G.; J. Org. Chem., 30,

4101, (1955).

7. Bose, A. K., Manhas, M. S., Ramer, R. N.; Tetrahedron, 21, 449, (1965).

8. Kumar,, A. Tyagi, M., Srivastav, V. K., ; Ind. J. Chem., 42B, 2142, (2003).

9. Sharma, S. D., Saluja, A. and Bhaduri, S.; Ind. J. Chem., 39B, 156, (2000).

10. Newkome, G. and Nayak, A.; Advances of heterocyclic Chem., 25, 83, (1979).

11. Desai, P., Chapaneri, K R., Desai, K. R. ; Asian J. Chem. 12, 308, (2000).

12. Parikh, K. A., Oza, P. S., Bhatt, S. B and Parikh, A. R., Ind. J. Chem. 39B,

716, (2000).

13. Vashi, K. and Naik, H.B. E-J. Chem., 1, 272, (2004).

14. Grzeszczyk, Barbara; Stecko, Sebastian; Mucha, Lukasz; Staszewska-

Krajewska, Olga; Chmielewski, Marek; Furman, Bartlomiej ; J. Antibiotics,

66(3), 161-163 (2013).

15. Mccomas, Casey Cameron; Liverton, Nigel J.; Habermann, Joerg; Koch, Uwe;

Narjes, Frank; Li, Peng; Peng, Xuanjia; Soll, Richard; Wu, Hao; Palani,

Anandan; et al ; PCT Int. Appl., WO 2013033971 A1 20130314 (2013).

16. Gomathy, S.; Gowramma, B.; Yadav, Swati; Antony, A. Shanish; Jubie, S.;

Kalirajan, R.; Elango, K. ;J. Pharm. Res., 5(11), 5120-5122 (2012). |

17. Akbari, Vikunjana K.; Patel, Pragnesh D.; Patel, Keshav C.; International J.

ChemTech Res., 5(1), 142-155 (2013).

18. Antre, R. V.; Oswal, R. J.; Thorat, D. B.; Shete, R. B.; International J. Drug

Design and Discovery 3(2), 749-752 (2012).

19. Garg, Neha; Chandra, Trilok; Lata, Suman; Saxena, K. K.; Kumar, Ashok;

Organic Chem.: An Indian J. 5(2), 208-214 (2009).


Page : 54

20. Raval, Jignesh P.; Patel, Hemul V.; Patel, Pradip S.; Patel, Nilesh H.; Desai, Kishor R.; Asian J. of Res. in Chem. 2(2), 171-177 (2009).

21. Bhusnure, Omprakash G.; Mokale, Sham S.; Nalwar, Yogesh S.; Vibhute, Yeshwant B.;; J. Pharm. Bio. Sci. 08 (2011).

22. Rajput, Chatrasal Singh; Sharma, Sanjeev; Yashovardhan; International J. Pharma. Bio Sc., 2(3), 200-209 (2011).

23. Smith Elizabeth M; Sorota Steve; Kim Hyunjin M; McKittrick Brian A; Nechuta Terry L; Bennett Chad; Knutson Chad; Burnett Duane A; Kieselgof Jane; Tan Zheng; et al ; Bioorg. Med. Chem. letters 20(15), 4602-6 (2010).

24. Sayyed, M. A.; Nalwar, Y. S.; Mokle, S. S.; Vibhute, A. Y.; Khansole, S. V.; Vibhute, Y. B.; International J. ChemTech Res. 1(3), 606-609 (2009).

25. Ramalakshmishmi, Natarajan; Deepa, Selvaraj; Antro, Jenny; Gopi; Arunkumar, Subramani; Puratchikody, Ayarivan; Bharathi, Raj Vijaya; International J. of Chem Tech Res. 1(4), 1000-1004 (2009).

26. Bhusare, S. R., Shinde, A.B., Pawar, R. P., Vibhute, Y. B.; Ind. J. Pharm. Sci., 66, 228, (2004).

27. Priyadarsani, R., Vijyaraj, R., Ravi, K. and Prabha, M.; Ind. J. Heterocyclic Chem., 14, 165, (2004).

28. Huibin, Z. W.Yubin, Z. Rui, H. Wenlong, L.Yunman and Z. Jinpei; Letters in drug Design & Discovery, 5, 39, (2008).

29. Kant, P. and R. K. Saxena, Ind. J. Heterocyclic Chem., 12, 312, (2003). 30. Shanmugapandiyan, P.; Denshing, K. S.; Ilavarasan, R.; Anbalagan, N.;

Nirmal, R.; International J. Pharma. Sci. Drug Res. 2(2), 115-119 (2010). 31. Deeb, A.; Bayoumy, B. E.; El-Mobayed, M.; Egyptian J. Pharma. Sci., 27(1-

4), 37-41 (1986). 32. Abdel-Rahman, A. E.; Mahmoud, A. M.; El-Naggar, G. M.; El-Sherief, H. A.;

Pharmazie, 38(9), 589-90 (1983). 33. Abdel-Rahman, A. E.; Mahmoud, A. M.; El-Naggar, G. M.; El-Sherief, H. A.;

Bulletin of the Faculty of Science, Assiut University, 11(1), 41-8 (1982). 34. Srivastava, S. K.; Ind. J. Chem., 41B, 2357, (2002). 35. Rai, N. R. and Suryavasani, J. P.; Ind. J. Chem., 45B, 1227, (2006). 36. Kumar, M. M. J. Vijay; Nagaraja, T. S.; Shameer, H.; Jayachandran, E.;

Sreenivasa, G. M.; J. Pharma. Sci. Res. 1(2), 83-92 (2009). 37. Jaju, Sandip; Palkar, Mahesh; Maddi, Veeresh; Ronad, Pradeepkumar;

Mamledesai, Shivalingarao; Satyanarayana, Darbhamulla; Ghatole, Mangala ;Archiv der Pharmazie (Weinheim, Germany), 342(12), 723-731 (2009).


Page : 55

38. Galletti, Paola; Quintavalla, Arianna; Ventrici, Caterina; Giannini, Giuseppe; Cabri, Walter; Penco, Sergio; Gallo, Grazia; Vincenti, Silvia; Giacomini, Daria; Chem Med Chem 4(12), 1991-2001 (2009).

39. H. A. Solieman, E. Abd, F. M. Latif, M. A Khalil and I. H. Elazab, Phosphorus, sulfur and Silicon, 117, 1001, (2002).

40. Reddy, P. S., Reddy, P. P. and T. Vasantha; Ind. J. Chem., 41B, 1946, (2002). 41. Guillermo, G. N., Teresa, G. L., Graciela, A., Robert, S., Jan, B., Erik, D. C.

and G. M. Rosario, Bioorg. Med. Chem. Lett., 14, 2253, (2004). 42. Grigoris, Z., Christos, F., Ioannis, P., George, B. F., F. George, P. Elizaveta,

N. Johan and K. Nicolas, Bioorg. Med. Chem., 14, 3341, (2006). 43. Zhang, H., Wang, Y., Zhao, R., Huang, W., L.Yunman, J. Zhou, Letters in

Drug Design & Discovery, 5, 1, 39, (2008). 44. Aoyama Y; Uenaka M; Kii M; Tanaka M; Konoike T; Hayasaki-Kajiwara Y;

Naya N; Nakajima M ; Bioorganic & medicinal Chem. 9(11), 3065-75 (2001). 45. Frick Wendelin; Bauer-Schafer Andrea; Bauer Jochen; Girbig Frank; Corsiero

Daniel; Heuer Hubert; Kramer Werner ; Bioorg. Med. Chem. 11(8), 1639-42 (2003).

46. Hassan, Khairy M.; El-Shafei, Ahmed K.; El-Kashef, Hussein S.; Mashaly, Mohamed M.; J. of Chem. Technology and Biotechnology, 32(2), 416-20 (1979-1982).


Page : 56

CHEMISTRY OF PYRIMIDINES: Pyrimidine is a six membered heterocyclic compound consisting of two

nitrogen atoms at 1 and 3 position of heterocyclic ring.

N

N

Pyrimidine

Generally pyrimidine derivatives such as 2-hydroxy pyrimidine, 2-mercapto

pyrimidine and 2-aminopyrimidine are studied. Pyrimidines have been isolated from

the nucleic acid hydrolysates.

Pyrimidines are among those molecules that make life possible has being

some of the building blocks of DNA and RNA. Several analogs of pyrimidines have

been used as compounds that interfere with the synthesis and functioning of nucleic

acids e.g. fluorouracil, which has been used in cancer treatment, Also there are some

thiouracil derivatives, which produce adverse reduction in susceptible patients and

found more potent and less likely to produce side effects and is being widely used[1].

There are several other important groups of pyrimidines with medicinal uses.

Pyrimidine ring carrying various substituent may be built up from two or three

aliphatic fragments by the principle synthesis or by a variety of other synthesis, which

are complimentary rather than alternative to it. A second type of synthesis is the

isomerisation or break down of another heterocycles such as a hydration of purine but

such roots are frequently used.

The first primary synthesis from aliphatic fragments was carried out by

Frankland et al., in 1848, since then a many distinct primary synthetic method have

been devised [2-11]. It is also possible to prepare pyrimidines from other heterocyclic

compounds such as pyrole [12], imidazole[13] and oxazoles[14-15], pyridines[16],

pyrazines[17], 1, 3, 5-triazines[18], oxazines[19], thiazines[20] by variety of

processes. Pyrimidine derivatives occurs in natural products [21]like nucleic acids and

vitamin-B have remarkable pharmaceutical importance [22-23]because of their

biological activities[24].The biological significance of the pyrimidine derivatives has

led us to the synthesis of substituted pyrimidines. As pyrimidine is a basic nucleus in

DNA & RNA, it has been found to be associated with diverse biological activities.


Page : 57

[25]The synthesis of substituted pyrimidine and many detailed reviews have been

appeared. [26-27].

GENERAL METHODS OF PREPARATION OF PYRIMIDINES:

Synthetic strategies involved four main routes based on the condensation of

two fragments, as illustrated by (I) to (IV). Of these strategies, the one illustrated by

(I) i.e. the condensation of a three carbon unit with an N – C – N fragment, appears to

be the most widely used, offering direct entry in to the pyrimidine nucleus.

N

CN

CC

C

CC

C

N

N

CC

C

N

CN

C

CC

C

N

CN

( I ) ( II ) ( III ) ( IV ) This approach has been called ‘the common synthesis because of its general

applicability to the synthesis of a whole range of pyrimidine derivatives.

1. The great versatility in this synthesis rests with the fact that one or both of the

groups of the three carbon fragment may be present as an aldehyde, ketone, ester

or nitrile group. β-Dialdehydes (or their equivalent), β-keto aldehyde, β-keto

esters, malonicester, β-aldehyde or β-keto nitriles and many other combinations of

these groups or their marked derivatives may be used. The nitrogen containing

fragment may be an amidines, urea, thiourea or guanidine and acetylacetone

serves as an excellent illustrative example in that it readily undergoes reaction

with formamidine, [28]guanidine, [29]urea, [30]thiourea[31]to produce the

correspond- ding 4, 6-dimethyl pyrimidine. (Scheme –I)

CH3 CO CH2 COCH3

NH2 C NH2

O

NH2 C NH2

S

NH CH NH2C NHNH2

CH3

N

N

Me

Me

N

N

Me

SHMe

N

N

Me

Me OH

N

N

Me

Me NH2

(Scheme –I)


Page : 58

The limitation of this reaction is that, in practice not all possible combinations of

reactants produce the expected products, as typified by the failure of malondialdehyde

to undergo condensation with formamidine to produce pyrimidine. It is often possible

however; to achieve transformations of this type by modification of the reaction

conditions and/or reactants. Thus 1, 1, 3, 3-tetraethoxy propane, a readily available

precursor of malondialdehyde, reacts with formamide over an alumina catalyst at

200°C to produce pyrimidine in 70% yield.

2. Hussain et al [32] have prepared pyrimidine derivatives by the condensation

between chalcone and guanidine nitrate. (Scheme-II)

O

F

ClCl+ NH2 C NH2

NH

HNO3

EtOH / OH

F

ClCl

N N

NH2 (Scheme – II)

3. 3, 5-dibromo-4-hydroxy substituted chalcones react with SBT in presence of

piperidine / pyrrolidine in DMF to give pyrimidines [33] (Scheme-III)

OH

Br

Br

C CH3

O

+

R2

CH

O

R1

OH

OH

Br

Br

C CH

O

CH

R2

R1

SBT/DMF - piperidine/

pyrrolidineexcess base

[O]

3,5-Dibromo-4-hydroxy acetophenone


Page : 59

OH

Br

BrN

NS

R2

CH2 Ph

R1

OH

Br

BrN

NR3

R2

R1

(Scheme – III) Where R1, R2, R3 = H

4. 4-(2-Amino phenyl)-6-(2, 4-dichloro-5-fluoro phenyl) pyrimidine is obtained by

condensing compound (I) and guanidine hydrochloride in presence of sodium

hydroxide in ethanol. [34] (Scheme-IV)

O

Ar Ar'+ NH2 C NH2

NH

HCl

EtOH / OH

N N

NH2

Ar' Ar

( I )

Ar = 2,4-(Cl)2-5-F-C6H5

Ar' = C6H5

(Scheme-IV)

5. The reaction of chalcone with guanidine hydrochloride in presence of potassium-t-

butoxide in t-butanol yielded corresponding 2-amino pyrimidine derivatives [35]

6. Abd-El-galil E. Amr et.al [36] synthesized aminopyrimidines by the reaction of

chalcones with guanidine hydrochloride in the presence of NaOH.

7. Rasaki [37] synthesised 2-aminopyrimidine by the reaction of chalcone epoxides

with guanidine carbonate in xylene.


Page : 60


Pyrimidines are an important class of drugs science they possess a wide range

of biological activities. A large number of derivatives are reported to exhibit

antitumor [38-41], antiviral [42], antifungal, anticancer [43], antibcteria [44], anti-

inflammatory [45-48], analgesic [49], Antagonist [50-51], antifolate [52],

antimicrobial [53], anti-HIV [54], antiproliferative [55], antiplatelet [56],

antithrombotic [57], antifilarial [58] activities, etc.

Khadse et. al. [59] prepared following type [V] of thiourea derivatives

possessing antituberculosis activity at 1.56 μg/ml against M.tuberculosis. N

N

NH2

NH2

NH C NH R

S [V]

6-Cyclopropyl-4-methyl-N-phenyl-2-pyrimidine [VI] synergistically

controlled pyrenophora terse on barley. [60]

NN

NH

Me

Ph N

N

N

NH2

NH2

CH3

N

R

[VI] [VII] Where R= H, Me

A series of pyrimidine derivatives of type [VII] have been synthesized as

potential Pneumocystis carrinii, Toxoplasma gondii and Dihydrofolate reductase

inhibitors as antitumor agents. [61]

6-Chloro-2-[(1-fuloro[2, 3-c]pyridine-5-ylethyl)thio]-4-pyrimidinamine and its

derivatives have been synthesized as broad spectrum of HIV-1 non-nucleoside reverse

transcriptase inhibitors. [62]

N

NX

NH2

NH2

R

Where R= 3,4,5-(OCH3)3,H,2-Cl

NN

F

O RR'

F

X

Where X = NH; R, R' = Me

[VIII] [IX]

L. Naesens et al [63] showed that some of the pyrimidine derivatives of type

[VIII] exhibited antiviral activity against DNA viruses or RNA viruses tested invitro.


Page : 61

R. Ragno [64]has synthesized a series of pyrimidine derivatives. Amongst

these, 2-cyclo pentyl amino-6-[1-(2, 6-difluoro phenyl)ethyl-3, 4-dihydro-5-methyl

pyrimidine-4(3H)-one [IX] was active against the Y181C HIV-1 mutant strain at

submicromolar concentration, with a resistance value similar to that of efavirenz, the

last FDA approved NNRTI for AIDS therapy.

Several novel 2, 4-diamino pyrimidines were synthesized and tested as

inhibitors of dihydrofolate reductase (DHFR) and compared with their activity against

DHFR derived from Mycobacteria and Escherichia coli. [65]

Highly potent dihydroalkoxybenzyloxopyrimidine (DABO) [X] derivatives

targeting the nonnucleoside inhibitors (NNI) binding site of Human

Immunodeficiency Virus (HIV), Reverse Transcriptase (RT) have been designed

based on the structure of the NNI binding pocket and tested for their anti-HIV

activity. [66]

NN

NH2

NNR

RR

R

N

NH

O

R2

R1

R1S S

Me

Where R1 = H,Me; R2 = Me,Ethyl, Isopropyl

[X] [XI]

Liu et al [67] synthesized three new two-photon absorption chromophores

based on a pyrimidine core [XI]. They were synthesized by aldol condensation in the

absence of any organic solvents. Their single-photon spectroscopic characterization as

well as their two-photon absorption properties is reported. In addition, strong

modulation of single-photon and two-photon fluorescent spectra of these molecules

by protonation is also discussed.

Many scientists have synthesized 2, 4, 6-trisubstituted pyrimidines. They have

been shown to possess diversely biological activities. As examples, compound [XII]

shows in vitro antimalarial activity against Plasmodium falciparum[68], with an MIC

value of 0.25 μg/ml. Compound [XIII] is a selective adenosine A1 receptor

antagonist[69], with high A1 affinity and selectivity. Compound [XIV] is a

phosphotidyli- nositol kinase inhibitor and can be used for the treatment of cancer

[70]. Compound [XV] shows antitubercular activity against Mycobacterium

tuberculosis at a concentration of 12.5 μg/ml[71].


Page : 62

NN

CH3N

NN

NHCH3

O [XII] [XIII]

NN

N

O

NN

NH

CH3

N

CH3

CH3

OOHCH3

[XIV] [XV]

Chikhliya et al [72] have studied and synthesized of pyrimidine derivatives

and their biological properties. Where R = aryl substituted [XVI].

NN

NH

R

S

O

O

N N

NN

O [XVI]

Thore synthesized [73]3, 5-bis-1, 4-dihydro-4-phenyl 2, 6-dimethyl pyridine-

2`-amino-6` phenyl pyrimidines [XVII].

NH

CH3CH3

R

N

N

NH2

R1

N

N NH2

R2

[XVII]


Page : 63

S. S. Bahekar and D. B. Shinde[74] have synthesized [2-amino-6-(4-

substituted aryl)-4-(4-substituted phenyl)-1, 6-dihydropyrimidine-5-yl]-acetic acid

derivatives [XVIII]. Synthesized compounds have shown good anti-inflammatory

activity against standard drugs.

NH

N NH2

R1

ROH O

R = Aryl, R1 = H,Cl,CH3

N

NN

N

N N

Ar

Ar

Ar = Substituted phenyl [XVIII] [XIX]

Om Prakash [75]and his co-worker reported the synthesis of 3, 9-diaryl and 3,

9-difuryl-bis-1, 2, 4-triazolo[4, 3-a][4, 3-c]-pyrimidines [XIX] as antibacterial agents.

Aldo Andreani [76]and his co-worker reported the new heterocyclic system

diimidazo-(1, 2-a:1, 2-c)-pyrimidine [XX] which is a key intermediate for the

synthesis of antitumour derivatives.

S

N N

NN

RR

N

NH

NH

NH2

N

NH

NH

NH2

[XX]

Nigel J. Liverton et.al. [77] have synthesized 4-methylbenzyl 4-[ (pyrimidin-2-

ylamino) methyl]piperidine-1-carboxylate (XXI), an orally bioavailable, brain

penetrant NR2B selective N-methyl-D-aspartate receptor antagonist. Demonstrated

efficacy in vivo rodent models of antinociception, allodynia, and Parkinson's disease.

[XXI]

Prasenjit Mondal et al. [78] have synthesized the novel mercapto-pyrimidine

and amino-pyrimidine derivatives of indoline-2-one as potential antioxidant and

antibaterial agents, 1- (2-mercapto-6- (substituted phenyl) pyrimidine-4-yl) -3- (2-

substituted phenyl imino) indolin-2-one and 1- (2 amino-6- (substituted phenyl)

pyrimidine-4-yl) -3- (2-substituted phenyl imino) indolin-2-one were synthesized

from different substituted chalconised indole 2, 3 dione.

O N

O

HN

N

N


Page : 64

H. M. Hassan and A. A. Farrag [79], have synthesized 2-[glycyl or Dl-valyl-

p-substituted phenylmethyleneamino] -pyrimdine derivatives [XXII, XXIII]. The

resulting novel amino acid derivatives were screened for their antimicrobial activity

and application against plant pathogenic fungus Botrytis cinerea, the causal agent of

cucumber plant (Cucmis. sativa L) gray mold disease.

[XXII] [XXIII]

Rajesh Vyas et al., [80], have synthesized 4- (4-chlorophenyl) -6- (3, 4, 5-

trimethoxyphenyl) -pyrimidin-2-amine (XXIV), which showed the antibacterial and

herbicidal activity.

(XXIV)

Naik et. al., [81] have synthesized 2-[{2 (Morpholino) -3-pyridinyl- 5- thio} -

2 oxoethyl oxadiazolyl]- amino- 4- (2, 4 dichloro- 5- fluorophenyl) - 6- (aryl)

pyrimidine (XXV), which showed antimicrobial activity.

(XXV)

Stephane pedeboscq et al., have [82] synthesized 4- (2-Methylanilino)

benzo[b] thieno [2, 3-d] pyrimidine (XXVI) and 4- (2-Methoxyanilino) benzo [b]

N

O

NH2

N N

.HCl N

O

NH2

N N

C3H7

.HCl

XXI XXII

N N

Cl

OCH3

OCH3

OCH3

NH2

Cl

F

Cl

N N

NHO

S

N

N

O

N

N

O

CH3


Page : 65

thieno[2, 3-d]pyrimidine (XXVII) and demonstrated positive results on anti cancer

activity.

(XXVI, XXVII)

It was thought interesting to prepare some new oxo pyrimidine, thio

pyrimidine, substituted pyrimidine-2-thione derivatives from substituted chalcones.

N

N

NH

S

H2N

CH3N

N

NH

S

H2N

OCH3


Page : 66

Reaction Mechanism :

CR'

O

R CH

OH

NH

NH2

X

R ..

..NH NH

X

N N

NH2-H

-+, -H

-

OH-

-H2O

NH N

X

R'

NNH2

X

R R'R R'

R R' R R'

X = O, S, NH


Page : 67

References: 1. Gavack, Mc; Chevalley, T. H. J.; Keni-gsberg, S. and Pearsib, S.; Bull N.Y.

Med. Coll., 16, 58 (1953).

2. Rinkes I. J.; Reel. Trav. Cairn Pays-Bus., 46268 (1927).

3. Howard, G. A.; Lythgoe, B. and Todd, A. R.; J. Chem. Soc., 476 (1944).

4. Whitehead, C. W. and Traversol, J. J.; J. Chem. Soc., 80, 2l85 (1958).

5. Bredercck, H.; Effcnberger, F. and Trciber, H. J.; Chem. Ber., 96, 1505

(1963).

6. Brown, D. J.; Chem. Heterocycl. Compel., 20, 16-51 (1970).

7. Inoue, S.; Saggimoto, A. J. and Nodiff, E. A.; J. Org. Chem., 26, 4504 (1961).

8. Van, Allan J. A.; Org. Synth., 32, 45, (1952).

9. Tayior, E. G. and Morriosn, R. W. Jr.; J. Org. Chem., 32, 2379 (1967).

10. Russell, P. B. and Hitchings, G. H.; J. Am. Chem. Soc., 74, 3443 (1952).

11. Krohnke, P.; Schmidt, E. and Zoecher, W.; Chem. Ber.; 97, 1163 (1964).

12. Ajcllo, T.; Gflzz. Chem. Ital., 70, 504 (1940).

13. Mitchell, H. K. and Nyo J. F.; J. Am. Chem. Soc., 69, 674 (1947).

14. Shaw and Saugowdz G.; J. Chem. Soc., 665 (1954).

15. Dorhow, A. and Hell, J.; Chem. Ber., 93, 1998 (1960).

16. Slreef, J. W. and Dcnhertog, H. J.; Rec. Trav. Chem. Pays-Bas; 88, 1391

(1969).

17. Crow, W. D. and Wentrup, C.; Tetrahedron Lett., 7, 3115 (1969).

18. Schaefer, F. C.; Huffman, K. R. and Peters, G. A.; J. Org. Chem., 27, 548

(1962).

19. Eiden, F. and Nagar, B. S.; Naturwissen Schaften, 50, 403 (1963).

20. Warrerb R. N. and Cairn, E. N.; Aust. J. Chem. 24, 785 (1971).

21. Parmar, J. M, Modha, J. J., Parikh, A. R.; Ind. J. Chem., 38B, 440, (1999).

22. Heda, P. B., Ghiya, B. J., Asian J. Chem., 11, 591, (1999).

23. Karale, B. K., Gill, C. H.; Ind. J. Chem., 41B, 1957, (2002).

24. Sing, G., Yadav, A. K.; Ind. J. Chem., 41B, 430, (2002).

25. Ghoneim, K. M. and Youssef, R. J.; Ind. Chem. Soc., 53, 914, (1986).

26. Kenner, G. W. and Todd, A.; “Heterocyclic Compounds” Ed. R. C. Elderfield,

Wiley, New York, 6, (1957).


Page : 68

27. Brown, D. J.; “The Chemistry of Heterocyclic Compounds” Ed. A.

Weissberger, Interscience, New York, 6, (1962).

28. Hunt, R. R., McOmie, J. F. M. and Sayer, E. R.; J. Chem. Soc., 525, (1959).

29. Haley, C. A. C. and Maitland, P.; J. Chem. Soc., 3115, (1951).

30. Hale, W. J.; J. Am. Chem. Soc., 36, 104, (1914).

31. Hunt, R. R.; McOmie, J. F. M. and Sayer, E. R.; J. Chem. Soc., 627, (1959).

32. Hussain, K. F. and Verma, B. L.; Asian J. Chem., 4, 86, (1986).

33. Kothari, S. and Verma, B. L.; Ind. J. Chem., 8B, 285, (1999).

34. Mahmoud, M. R. and Radwan, A. M.; Ind. J. Chem., 35B, 915, (1996).

35. Murthy, Y. L. N. and Jagmohan, G.; Ind. J. Heterocyclic Chem., 8, 277-280

(1999).

36. El-Gail, Abd, Amr E.; Ind. J. Heterocyclic Chem., 10, 49-58 (1999).

37. Osisanya, Rasaki Abayomi and Oluwadiya, James Olabisi; J. Heterocyclic

Chem. 26, 947 (1989).

38. Sobolev, A.; J. Org. Chem., 67, 401, (2002).

39. Zhang, N., Ayral-Kaloustian, S, Nguyen, T., Hernandezb, R. and Beyerb, C.;

Bioorg. Med. Chem. Lett., 17, 3003, (2007).

40. Mohamed, N. R., Talaat, M. M. El-Saidi, Y. M. Alia and Elnagdi, M. H.,

Bioorg. Med. Chem., 15, 6227, (2007).

41. Rakib, E. M., Abouricha, S., Hannioui, A., Benchat, N., Ait M’barek, L. and

Zyad, A.; J. Iranian Chem. Soc., 33, 272, (2006).

42. Baraldi, P. G., Pavani, M. G., Nunez, M., Brigid, P., Vitali, B., Gambari, R.,

Romagnoli, R.; Bioorg. Med. Chem. Lett., 10, 449, (2002).

43. Kamela, A. M. and Munsonb, B.; J. Am. Soc. Mass Spectr., 18, 1477, (2007).

44. Zhang, N., Ayral-Kaloustian, S., Nguyen, T., Afragola, J., Hernandez, R.,

Lucas, J. Gibbons, J. and Beyer, C.; J. Med. Chem., 50, 319, (2007).

45. Prakash, O., Kumar, R., Ravi Kumar, Tyagi, P., Kuhad, R.C.; Euro. Med.

Chem., 42, 868, (2007).

46. Sondhi, S. M., Jain, S., Dinodia, M., Shuklab, R. and Raghubir, R.; Bioorg.

Med. Chem., 15, 3334, (2007).

47. Molina, P., Aller, E., Lorenzo, A., Lo´pez-Cremades, P., Rioja, I., Ubeda, A.,

Terencio, M. C. and Alcaraz, M. J.; J. Med. Chem., 44, 1011, (2001).

48. Bahekar, S. S., Shinde, D. B., Acta Pharm., 53, 223, (2003).


Page : 69

49. Sondhi, S. M., Johar, M., Rajvanshi, S., Dastidar, S. G., Shukla, R., Raghubir,

R., Lown, J. W.; Aust. J. Chem., 54, 69, (2001).

50. Bruno, O., Brullo, C., Schenone, S., Ranise, A., Bondavalli, E., Barocelli E.,

Tognolini, M., Magnanini, E., Bollabeni, V.; Farmaco, 57, 753, (2002).

51. Lanier, M. C., Feher, M. N., Ashweek, J., Loweth, C. J., Rueter, J. K., Slee, D.

H., Sullivana, S. K. and Browna M. S.; Bioorg. Med. Chem., 15, 5590, (2007).

52. Liverton, N. J., Bednar, R. A., Bednar, B., Butcher, J. W., Claiborne, C. F.,

Claremon D. A. and Koblan, K. S., J. Med. Chem., 50, 807, (2007).

53. Gangjee, A., Zeng, Y., McGuire, J. J. and Kisliuk, R. L.; J. Med. Chem., 48,

5329, (2005).

54. Eid F. A., El-Wahab, A. F. A., El-Hag Ali, G.A. M., Khafagy, M. M., Acta

Pharm., 54, 13, (2004).

55. Coe, D. M., Meyers, P. L., Paryl D. M., J. Chem. Soc., 2, 157, (1990).

56. Xiaoling L. and Mei-Lin, G., Bioorg Med. Chem., 14, 153, (2006).

57. Bruno, O., Brullo, C., Schenone, S., Bondavalli, F., Ranise, A., Tognolini, M.,

Impicciatore, M., Ballabeni, V. Barocelli, E., Bioorg Med. Chem., 14, 121,

(2006).

58. Katiyar, S. B., I. Bansal, J. K. Saxena, P. M. S. Chauhan; Bioorg Med. Chem.

Lett., 15, 47, (2005).

59. Khadse B. G., Lokhande S. R. and Khaimar, V. L., Bull. Haffkine Inst., 73, 29,

(1979).

60. Ger. Offen. DE., 4, 422, 776., C. A., 125944e, 122, (1995).

61. Gangiee A. and Adaer G.; J. Med. Chem., 42, 2447, (1999).

62. Ludovici D. W. and Janssen, P. A. J.; Bioorg. Med. Chem. Lett., 11, 2235,

(2001).

63. Otzen T. and Seydel, J. K.; J. Med. Chem., 47, 240, (2004).

64. Rosowsky A. and Queener, S. F.; J. Med. Chem., 47, 1475, (2004).

65. Ragno R. and Colla, P. L.; J. Med. Chem., 47, 928, (2004).

66. Naesens L. and De Clerq, E.; J. Med. Chem., 45, 1918, (2002).

67. Liu, B. Hu, X.; Liu, J.; Zhao Y. and Huang, Z.; Tetrahedron Lett., 48, 5958,

(2007).

68. Agarwal, A.; Srivastava, K.; Purib, S. K.; Chauhana, P. M. S.; Bioorg. Med.

Chem., 13, 4645, (2005).

69. Chang, L. C. W.; Spanjersberg, R. F.; Drabbe, V. F.; Ku¨nzel, J. K.; Mulder-

Krieger, T.; Hout, G.; J. Med. Chem., 47, 6529, (2004).


Page : 70

70. Bailey, J. P.; Giles, M. B., Pass, M., PCT Int. Appl., WO2006005914 A1

20060119, (2006).

71. Agarwal, A. Srivastava, K. Puri, S. K. Sinha, S. Chauhana, P. M. S.; Bioorg.

Med. Chem. Lett., 15, 5218, (2005).

72. Naik T. A. and Chikhliya, K. H.; E-Jour. Chem., 4, 60, (2007).

73. Thore, S. N.; Asian J. Chem., 19, 4429, (2007).

74. Bahekar S. S. and Shinde, D. B.; Acta Pharm., 53, 223, (2003).

75. Prakash Om., Rajesh Kumar, Ravi Kumar, P. Tyagi, R.C. Kuhad; Euro. Med.

Chem., 42, 868, (2007).

76. A. Andreani, M. Granaiola, A. Leoni, A. Locatelli, R. Morigi, M. Rambadli,

G. Giorgi and L. Salvini, Arkivok xi 32, (2002).

77. Nigel, J.; Liverton, Rodney A.; Bednar, Bohumil; Bednar John W. Butcher, J.

Med. Chem., 504, 807–819 (2007).,

78. Prasenjit, Mondal; Soma, Jana & Lakshmi, Kanta Kanthal; The Pharma

Research, 3; 2010).

79. Hassan, H. M. et al J. Chem. Pharm. Res., 32, 776-785, (2011).

80. Vyas, R; Udaibhan, Gahlot S; Verma, B.L; Ind. J. Hetero. Chem; 13, 115

(2003).

81. Naik, T.A. and Chikhalia, K.H.; E-Journal of Chem.; 41, 60-66 (2007).

82. Pedeboscq, S; Gravier, D; Casadebaig, F; Hou, G; et at; Eur. J. Med. Chem.;

45, 2473-2479 (2010).

[00] title pages and new index -...

Documents