Synthesis and Biological Activities of Some Novel Heterocyclic Compounds Containing Thiazolidinone Derivatives

 

Puttaraj C., Chetan M. Bhalgat, Sandeep K. Chitale and B. Ramesh*

Department of Pharmaceutical Chemistry, S.A.C. College of Pharmacy, B.G.Nagara- 571448, Mandya.

*Corresponding Author E-mail: rambha­_vin@yahoo.com

ABSTRACT:

Amino group of thiazole moiety have been treated with various aromatic aldehydes gave

corresponding Schiff's bases, 3A-G. These Schiff's bases have been reacted with thioglycolic acid, anhydrous zinc chloride and N,N′-dimethyl Formamide as a solvent to get corresponding novel thiazolidinone derivatives, 4A-G. Structures of all the newly synthesized compounds were confirmed by IR, ¹H NMR, and mass spectral data. The synthesized compounds were evaluated for their antioxidant activity. Few compounds were found with potent antioxidant activity.

 

KEYWORDS: Thiazole, Thiazolidinone, Sciff’s bases, Antioxidant activity

 

 

INTRODUCTION:

Heterocyclic synthesis has emerged as powerful technique for generating new molecules useful for drug discovery¹. Heterocyclic compounds provide scaffolds on which pharmacophores can arrange to yield potent and selective drugs².

The presence of thiazolidinone moiety in the structure of several naturally occurring molecules with important antibiotic, immunosuppressive and antitumor activities has been known for several year^3-6. Small ring heterocycles containing nitrogen and sulfur have been under investigation for a long time because of their important medicinal properties. Among the wide range of heterocycles explored to develop pharmaceutically important molecules, thiazoles have played an important role in medicinal chemistry. A survey of literature has shown that compounds having thiazolidinone nucleus possess a broad range of biological activities such as antibacterial⁷, antifungal⁸, antihyperglycemic⁹, anti-inflammatory¹⁰, antitubercular¹¹, antioxidant¹², antitumor¹³, anti-HIV¹⁴, anesthetic¹⁵, anti-viral¹⁶, anticonvulsant¹⁷, diuretics¹⁸, nematicidal¹⁹, and antihistaminic activity²⁰. Recently reported some of work on the synthesis, transformations and wide rang biological properties of various 4-thiazolidinones molecules^21-27.

In the view of the facts mentioned above, we have synthesized some novel thiazolidinone derivatives, 4A-G. The novel derivatives were characterized by spectral data and these compounds were tested for their antioxidant screening.

 

MATERIALS AND METHODS:

I] Experimental section:

Reactions and purity of compounds were monitored by TLC (silica gel G60) using Chloroform: Methanol (9:1) solvent system and the spots were identified by iodine vapor chamber. Melting points were determined in open capillary using paraffin bath and are uncorrected. The IR spectra of the compounds were recorded on NICOLET380 FT-IR spectrophotometer using KBr pellets. ¹H NMR spectra were recorded in DMSO on a 300 MHz Shimadzu FT-NMR (δ in ppm) relative to TMS as internal standard. The mass spectra were recorded on Triple Quadruple LC-MS with ESI source. Mfg. SCIEX at 70eV.

 

Preparation of p-acetamido acetophenone (1), 2-Amino-4-(4'-acetanilido)-thiazole (2) and 2-[(Substituted-benzylidene) amino]-4-(4'-acetanilido)-thiazole (3 A-G)

The compounds p-acetamido acetophenone (1), 2-Amino-4-(4'-acetanilido)-thiazole (2) and 2-[(Substituted-benzylidene) amino]-4-(4'-acetanilido)-thiazole (3 A-G) were prepared according to method used by Sharma et al²⁸.

 

Preparation of N-{4-[2-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)-1,3-thiazol-yl] phenyl} acetamide (4A-G)

An equimolar amounts of Schiff’s base (0.01 mole) and thioglycolic acid (0.01 mole) and catalytic amount of anhydrous zinc chloride in to a 100 ml round bottom flask containing 30 ml of DMF was refluxed for about 18 h. Then the reaction mixture was poured into crushed ice. The solid obtained was filtered, washed with ethanol, dried and recrystallized from suitable solvents.

 

Figure 1: Scheme of synthesis

 

a. Acetic anhydride, b- Thiourea, Iodine, c- Aromatic aldehyde, Glacial acetic acid,

b. Thioglycolic acid, N,N’Dimethyl formamide, Zinc chloride.

 

 

The Schematic representation has been given in Scheme 1 (Fig-1). The physical data and spectral data of the synthesized compound were given in table 1 and table 2 respectively.

 

II] In vitro antioxidant activity:

a.       Nitric oxide scavenging activity

The reaction mixture (6 mL) containing sodium nitroprusside (10 mM, 4 mL), phosphate buffer saline (pH 7.4, 1 mL) and test samples or standard, ascorbic acid solution in dimethyl sulphoxide (1 mL) at various concentrations (12.5, 25, 50, 100 µg/ mL) was incubated at 25 °C for 150 min. After incubation, 0.5 mL of reaction mixture containing nitrite ion was removed, 1 mL of sulphanillic acid reagent was added to this, mixed well and allowed to stand for 5 min for completion of diazotization. Then, 1 mL of naphthyl ethylene diamine dihydrochloride was added, mixed and allowed to stand for 30 min in diffused light. A pink colored chromophore was formed. The absorbance was measured at 640 nm²⁹.

 

b.       Scavenging of hydrogen peroxide:

A solution of hydrogen peroxide (20 mM) was prepared in phosphate buffer saline (pH 7.4). Various concentrations (12.5, 25, 50, 100 µg/mL) of 1 mL of the test samples or standard, ascorbic acid in methanol were added to 2 mL of hydrogen peroxide solution in phosphate buffer saline. The absorbance was measured at 230 nm after 10 min³⁰.

 

Table 1: Physical data of synthesized compound: 4(A-G)

Code	Chemical name	Mol. formula	Mol. weight	Recry. Solvent	M.P. oC	% Yield
4A	N-(4-{2-[2-(4-hydroxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C20H17N3O3S2	411.49	Chloroform	240	42
4B	N-(4-{2-[2-(4-chlorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C20H16ClN3O2S2	429.94	Chloroform	230	68
4C	N-(4-{2-[2-(4-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C20H16N4O4S2	440.49	Ethanol	237	44
4D	N-(4-{2-[2-(3,4,6-trimethoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C23H23N3O5S2	485.57	Methanol	310	46
4E	N-(4-{2-[2-(4-hydroxy-3-methoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C21H19N3O4S2	441.52	Methanol	235	51
4F	N-(4-{2-[2-(3-nitrophenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C20H16N4O4S2	440.49	Chloroform	210	67
4G	N-(4-{2-[2-(4-hydroxy-3-ethoxyphenyl)-4-oxo-1,3-thiazolidin-3-yl]-1,3-thiazol-4-yl}phenyl)acetamide	C22H21N3O4S2	455.54	Chloroform	307	53

 

Table 2. Spectral data of synthesized compound:

Compound Code	IR (KBr cm-1)	1H NMR (DMSO δ ppm)	Mass M+ m/z
4A	1159 (C-S), 1655 (C=O), 3304 (NH), 1637 (C=N), 2927 (C-H), 1536 (C=C), 3416 (OH).	2.49 (s, 3H, C-CH3), 3.31 (s, 2H, CH2), 4.48 (s, 1H, OH), 5.53 (s, 1H, CH), 6.52-6.95 (m, 9H, Ar-H), 9.94 (s, 1H, NH)	411
4B	1180 (C-S), 1671 (C=O), 3303 (NH), 1637 (C=N), 1491 (C=C), 2878 (C-H), 1258 (C-N), 839 (C-Cl)	2.38 (s, 3H, C-CH3), 3.29 (s, 2H, CH2), 5.48 (s, 1H, CH), 7.14-7.43 (m, 9H, Ar-H), 9.87 (s, 1H, NH)	429
4C	1180 (C-S), 1675 (C=O), 3307(NH), 1597 (C=N), 1518 (C=C), 2915 (C-H), 1370 (NO), 1180(C-N)	2.14 (s, 3H, C-CH3), 3.12 (s, 2H, CH2), 5.67 (s, 1H, CH), 6.72-6.98 (m, 9H, Ar-H), 8.62 (s, 1H, NH)	440
4D	1121 (C-S), 1654 (C=O), 3399 (NH), 1595 (C=N), 1459 (C=C), 2855 (C-H), 1234 (C-N)	2.04 (s, 3H, C-CH3), 2.93 (s, 2H, CH2), 3.86 (s, 9H, [OCH3]3), 5.53 (s, 1H, CH), 6.34-6.88 (m, 7H, Ar-H), 8.83 (s, 1H, NH)	485
4E	1086 (C-S), 1654 (C=O), 3423 (NH), 1635 (C=N), 1459 (C=C), 2927 (C-H), 1086 (C-N), 3512 (OH)	1.96 (s, 3H, C-CH3), 3.17 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 4.67 (s, 1H, OH), 5.49 (s, 1H, CH), 6.73-7.15 (m, 8H, Ar-H), 9.13 (s, 1H, NH)	441
4F	1179 (C-S), 1673 (C=O), 3303 (NH), 1597 (C=N), 1527 (C=C), 1404 (C-H), 1179 (C-N), 1349 (NO)	2.14 (s, 3H, C-CH3), 3.28 (s, 2H, CH2), 5.68 (s, 1H, CH), 6.98-7.55 (m, 9H, Ar-H), 9.06 (s, 1H, NH)	440
4G	1095 (C-S), 1637 (C=O), 1597 (C=N), 1560 (C=C), 3393 (NH), 2833 (C-H), 1226 (C-N), 3465 (OH)	1.27 (t, 3H, CH3 of ethoxy), 2.49 (s, 3H, CO-CH3), 3.19 (s, 2H, CH2 of thiazolidinone), 3.76 (s, 2H, CH2 of ethoxy), 4.06 (s, 1H, OH), 5.53 (s, 1H, CH), 6.45-7.67 (m, 8H, Ar-H), 9.19 (s, 1H, NH)	455

 

 

For all the above antioxidant methods, experiments were done in triplicate and average is taken, the % inhibition at different concentration was calculated by the following formula

% Inhibition= [1-(V_t/V_c)] × 100

Where, V_t = mean absorption of test compound, V_c= mean absorption of control

The IC₅₀ value was derived from the % inhibition at different concentration.

The comparison of IC₅₀ by both the techniques were given in table 3.

 

RESULTS AND DISCUSSION:

Molecules prepared for the biological testing do not always turn out as potential new compounds but may be intended to serve as models for evaluation of hypothesis. The thiazolidinone contained moieties independently are antibacterial and antifungal agents. The present work is to synthesize certain derivatives of thiazolidinone fused with p-acetamidophenone thiazole and aromatic aldehyde ring and were studied for their antioxidant activity. Here when these moieties are screened for antioxidant studies showed good antioxidant properties. Thus an expected substituted thiazolidinone with p-acetamidophenone thiazole and aromatic aldehyde ring exhibited moderate to good antioxidant activity when compared to the standard.

 

There is no such a thing as completely safe drug. Drugs are powerful tools which alter physiological processes for the better or for the worse. A society which wishes to benefit from them will not achieve all the benefits open to it, if it ignores the fact and seeks for impossible standards of harmlessness. The antioxidant testing showed that few compounds have promising activity at low dosage levels.

 

CONCLUSION:

The thiazolidinone fused with p-acetamidophenone thiazole and aromatic aldehyde ring substituted thiazolidinone derivatives 4A, 4D and 4G showed potent antioxidant. The antioxidant activity may be due to the free OH group. Therefore, more focus on compound 4A, 4D and 4G in direction to produce potent biodynamic molecule is necessary.

 

Table 3. IC50 values of thiazolidinone derivatives 4(A-G) and standard ascorbic acid.

 

Compound	IC50 ± S.D. in μg/ml
	Hydrogen peroxide	Nitric oxide
Ascorbic acid	44±0.01	39±0.01
4A	37±0.03	24±0.01
4B	<100	<100
4C	<100	<100
4D	<100	45±0.01
4E	<100	58±0.02
4F	84±0.04	88±0.02
4G	22±0.03	46±0.01

 

Above results establish the fact that thiazolidinone fused with p-acetamidophenone thiazole and aromatic aldehyde ring can be a rich source for exploitation. Hence, in search of new potent biodynamic agent, it may be worthwhile to explore the possibility in this area by fusing different aromatic aldehyde ring with thiazolidinone.

 

ACKNOWLEDGEMENTS:

The authors are thankful to administration of SAC College of pharmacy, B.G.Nagara for providing research facilities and encouragement. The authors are also thankful to Dept. of USIC Karnatak University, Dharwad for providing Spectra.

 

REFERENCES:

1.        Hermakens PH, Ottenheijm HC and Rees DC. Solid-phase organic reactions II: A review of literature. Nov95-nov96.Tetrahedron. 1997; 53: 5643.

2.        Gordon E, Barrett RW, Dower WJ and Foder SP. Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. J Med Chem. 1994; 37: 1485.

3.        Mulzer J, Mantoulider A and Ohler E. Synthesis and biological evaluation of some thiazolidinone derivatives of steroid as antibacterial agents. Eur J Med Chem. 2009; 44 (6): 2597-600.

4.        Badorc A, Bordes MF, Decointel P, Savi P, Lale A, Petitou M, et al. Synthesis and pharmacological examination of some thiazolidinone derivatives of naphtho[2,1- b ]furan. J Med Chem. 2006; 68 (6): 719-725.

5.        Vagdevi HM, Vaidya VP, Latha KP and Padmashali B. Synthesis and pharmacological examination of some thiazolidinone derivatives of naphtho[2,1- b ]furan. Ind J Pharm Sci. 2006; 68 (6): 719–725.

6.        Rzasa M, Shea HA and Romo D. Solid and solution phase synthesis of α-keto amides via azetidinone ring opening:Application to the synthesis of poststatin. Tetrahedran Lett. 1999; 40 (10): 1827-1830.

7.        Sup RC, Sup RY and Bang CW. Synthesis and anti-inflammatory activity of [2-(benzothiazol-2-ylimino)-4-oxo-3-pheylthiazolidin-5-yl]-acetic acid derivatives. J Korean Chem Soc. 1995; 47 (93): 237-240.

8.        Sonwane SK and Srivastava SD. Synthesis and biological significance of 2-amino-4-phenyl-1,3-thiazole derivatives. Proc Nat Acnd Sci India. 2008; 78 A(II): 129-36.

9.        Imaran M, Sharar YM and Khan SA. Synthesis and in vitro antimicrobial study of schiff base and thiazolidinone of 1-cyclopropyl-6-fluoro-7-[4-(2,3-dichlorophenyl)piperazin-1-yl]-4-quinolone. Acta Pol Pharm Drug Res. 2009; 66: 51.

10.      Vazzanaa I, Terranovaa E and Mattiolib FS. Synthesis and antimicrobial activity of 2-phenyl-3-{1-cyclopropyl-6-fluoro-7-[4-methylpiperazin-1-yl]-4-quinolone}-carboxamido-3-thiazolidin-4-ones. Pharm Chem J. 2004; 43 (6): 364.

11.      Dandia A, Singh R and Arya K. A new strategy for the synthesis of novel spiro[indoline-3,2'-thiazolo[5,4-e]pyrimido[1,2-a]pyrimidine] derivatives. Acta Pol Pharm Drug Res. 2004; 179: 551.

12.      Kus C, Ayhan-Kilcigil G, Can Eke B and Iscan M. Synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver. Arch Pharm Res. 2004; 27: 156-162.

13.      Faidallah HM, Al-Saadi MS, Rostom SA and Fahmy HT. Synthesis of some sulfonamides, disubstituted sulfonylureas or thioureas and some structurally related variants, A class of promising antitumor agents. Med Chem Res. 2007; 16 (6): 300.

14.      Ravichandran V, Mourya VK and Agrawal RK. QSAR analysis of some novel sulfonamides incorporating 1,3,5-triazine derivatives as carbonic anhydrase inhibitors. Digest J Nanomat Biostruct. 2008; 19 (9): 3.

15.      Surray AR. Synthesis, antibacterial and antifungal activities of 3-(1,2,4-triazol-3-yl)-4-thiazolidinones. Ind J Chem. 2006; 45 B: 1227-1230.

16.      Terzioglu N, Karali N, Gursoy A and Pannecouque C. N,N'-(Phenyliminodimethylene) diprop-2-enamide hemihydrates. Acta Pol Pharm Drug Res. 2009; 65 (6): 1343.

17.      Gursoy A and Ferziglu N. Synthesis and in vitro antimicrobial study of schiff base and thiazolidinone of 1-cyclopropyl-6-fluoro-7-[4-(2,3-dichlorophenyl)piperazin-1-yl]-4-quinolone. Turk J Chem. 2005; 29: 247.

18.      Raikwar DK, Srivastava SK and Srivastava SD. Synthesis of Some New Arylidenes-Substituted Phenyl-1,3,4 thiadiazol-4-oxo-thiazolidines (VIII): Antimicrobial and Diuretic Activities. J Ind Chem Soc. 2008; 39 (43): 78.

19.      Srinivas A, Nagaraj A and Reddy CS. Synthesis and biological study of novel methylene-bis-benzofuranyl-[1,5]-benzothiazepines. J Hetero Chem. 2008; 45: 999.

20.      Diurno MV, Mazzoni O, Piscopo E, Calignano A, Giordano F and Bolognese A. Synthesis and Antihistaminic Activity of Some Thiazolidin-4-ones. J Med Chem. 1992; 35: 2910.

21.      Ocal N, Yolacan C, Kaban S, Leonor Y, Vargas M and Kouznetsov VJ. Transformations of Schiff bases derived from quinoline-8-carbaldehyde, Synthesis of C-8 substituted quinolines. Hetero Chem. 2001; 38: 233-6.

22.      Mendez LY, Kouznetsov V, Poveda JC, Yolaçan C, Ocal N and Aydogan F. Transformations of 4-N-arylamino-4-(8-quinolinyl)-1-butenes and 3-aryl-2-(8-quinolinyl)-4-thiazolidinones. Hetero Commun. 2001; 7: 129-134.

23.      Aydogan F, Ocal N, Turgut Z and Yolacan C. Transformations of aldimines derived from pyrrole-2-carbaldehyde and Synthesis of thiazolidinone-fused compounds. Bull Korean Chem Soc. 2001; 22: 476-80.

24.      Shashikant R, Prajact K, Nachiket SD, Sunil AN, Deepak SM, Smita KP, et al. Synthesis and Biological Evaluation of Some 1,3,4-Thiadiazoles. J Chem and Pharm Res. 2009; 1 (1): 191-198.

25.      Sonwane SK, Srivastava SD and Srivastava SK. Synthesis and Antimicrobial Activity of Some 2-[(4-Substituted-Phenyl-3-Chloro-Azetidin-2-One)-5-(2'-Methylamino-4-Phenyl-1',3'-Thiazolyl-]-1,3,4-Thiadiazoles. J Sci Islamic Republic of Iran. 2009; 20 (3): 227-232.

26.      Sharma SC. Synthesis of new fungicides, 2-(4'-arylthiazolyl-2'-imino)-3-aryl-4- thiazolidones. Bull Chem Soc Japan. 1967; 40: 2422-2424.

27.      Akerblom EB. Synthesis and structure activity relations of a series of antibacterially active-5-(5-nitro-2-furfurylidene)thiazolones,5-(5-nitro-2-urylpropenylidene)-thiazolones, and 6-(5-nitro-2-furyl)-4H-1,3-thiazinones. J Med Chem. 1974; 17: 609-615.

28.      Sharma GK, Kumar S and Pathak D. Synthesis, antibacterial and anticancer activities of some novel imidazoles. Der Pharmacia Lett. 2010; 2: 223-230.

29.      Marcocci L, Packer L, Droy-lefaix MT, Sekaki A and Gondes-albert M. Antioxidant action of Ginkgo biloba extract EGb 761.  Methods Enzymol. 1994; 234: 462-473.

30.      Jayaprakasha GK, Jaganmohan RL and Sakariah KK. Antioxidant Activities of Flavidin in Different invitro Model Systems. Bioorg. Med. Chem. 2004;12: 5141-5146.

 

 

 

 

 

Received on 28.03.2011          Modified on 05.04.2011

Accepted on 10.04.2011         © RJPT All right reserved