INTRODUCTION:

There are numerous biologically active molecules with five-membered rings, containing two hetero atoms. Thiazolidinone is an important scaffold known to be associated with several biological activities. A comprehensive review has been written on 4-thiazolidinones in 1981¹.1,3-Thiazolidin-4-ones are heterocycles that have an atom of sulfur at position 1,nitrogen atom at position 3 and a carbonyl group at position 4. It is a sulfur analogue of oxazolidine. Thiazolidines may be synthesized by a condensation reaction between a thiol and an aldehyde or ketone. It is a reversible reaction.

Therefore many thiazolidines are labile towards hydrolysis in aqueous solution. Hydrolysis of the thiazolidine generates the thiol and an aldehyde from which it was synthesized².

BIOLOGICAL ACTIVITIES OF THIAZOLIDINE DERIVATIVES:

1. ANTI MICROBIAL ACTIVITY:

Anbalagan et al³., synthesized a series of 2-[(Thiazolidin-4-one)phenyl]-1H-phenylbenzimidazole. The synthesized compounds were screened for anti-bacterial activity and anti-fungal activity by using gram positive and gram negative bacterial species and fungal species by using nutrient agar medium, paper disc diffusion method. The synthesized compounds have shown significant anti-bacterial activity.

P. Sudhir Kumar et al⁴., synthesized some Novel Thiazolidin-4-one substituted 1,2,4-Triazoles.The synthesized compounds were tested on nutrient medium against gram positive and gram negative bacteria.All the compounds showed a very good anti-bacterial activity and the significant compounds like VIIIe and VIIIf were found to possess broad spectrum activity.

VIIIe: R=2-Hydroxy phenyl , VIIIf: R=2-Methoxy phenyl

Prasad et al⁵., synthesized Novel 2-aryl-thiazolidin-4-one derivatives. The synthesized compounds were screened for anti-microbial activities against gram +ve and gram-ve bacteria and six pathogenic fungal species. Compounds 8a-8d displayed significant anti-bacterial efficacy specially against Kiebsiella pneumonia.

8a, 8b, 8c, 8d: R=

R₁=H,R₂=H, R₄=H R₅=H.

8a:R₃=H, 8b:R₃=CF₃,8c:R₃=Br,8d:R₃=Cl.

Haricharan Lal et al⁶., synthesized 1,2,4-triazole substituted thiazolidinone and azetidinone derivatives. The synthesized compounds were evaluated for their antibacterial and anti-fungal activities by using cup-plate method.Compounds 9 and 10 shown moderate activity.

compound 9:X=Br, R=H, compound 10:X=Br, R=OH

Swarup Jyoti Chattarjee et al⁷., Synthesized some Thiazolidin-4-one substituted 1, 2, 4-triazoles . The synthesized compounds were studied for anti-microbial activities by cup-plate method using various gram stains of microbes and the standard drugs like ampicillin and Griseofulvin. The thiazolidine-4-one substituted 1, 2, 4- triazole and 3-methoxy benzofuran moieties at 3rd position might be largely responsible for the marked bactericidal activity. VIIIe and VIIf showed significant anti-bacterial activity.

Sudhakar Bhusare and Yeshwant Vibhute et al⁸., synthesized some new 2,3-diaryl-1,3-thiazolidin-4-ones and tested for anti-bacterial activity against bacterial strains by using nutrient agar disc diffusion method. The compounds have shown effective anti-bacterial activity.

Shiradkar et al.⁹, reported a series of N-{4-[(4- amino-5-sulphanyl-4H-1, 2, 4-triazol-3-yl) methyl]-1, 3-thiazol-2-yl}-2-substituted amide derivatives. These compounds were tested for their preliminary in-vitro antibacterial activity against S. aureus, E. coli, P. aeroginosa and S. typhosa and then were screened for antitubercular activity against M. tuberculae H37Rv strain by both micro dilution assay method. Compound [II] and [III] showed best activity. The compounds showing more than 90% inhibition were obtained by S-alkylation with acetonitrile. It was noted that the cyano group did not have any role in increasing the activity.

[II] R=NHCOCH_3,Ar=3-NO₂C₆H₄

[III] R=NHCOC₆H₅, Ar=3-NO₂C₆ H₄

Upadhyay A. et.al¹⁰., Several new N-[(4-oxo-2-substituted aryl-1, 3- thiazolidine)-acetamidyl]-5-nitroimidazoles were synthesized from N-(arylidene amino acetamidyl)-5- nitroindazoles. The reactions were carried out by both conventional as well as microwave method. The newly synthesized compounds were evaluated for their antimicrobial activity against bacterial and fungal strains. The compound [IV] and [V] show the maximum antibacterial activity (MIC 11 and 10 mg/mL) against Escherichia coli and antifungal activity (MIC 9 and 8 mg/mL) against Fusarium oxysporum.

[IV]Ar=2-OHC₆H₄, [V] Ar=3-OHC₆H₄

P. Jaya Preethi et al¹¹., synthesized a series of 4-thiazolidinones derivatives. These compounds were screened for anti-tubercular, antibacterial and anti-fungal activities. Anti-Tubercular activity mycobacterium tuberculosis and MIC level of the compounds was less than 6.25 μg/ml.

Compound IIIa, IIIc IIId, IVa, IVc and IVd exhibited good antibacterial activity on Gram-positive and Gram-negative microorganisms. All the synthesized compounds exhibited good Antifungal activity.

Nareshvarma Seelam and S. P. Shrivastava et al¹²., a series of thiazolidinone and their 5-arylidenederivatives containing 4-(4-methyl benzamido)-benzoyl moiety were synthesized via the reaction of benzocaine with appropriate chemical reagents. These compounds were screened for their antibacterial activity against Gram-positive bacteria (Bacillus subtilis and Bacillus thuringiensis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and antifungal activity against Botrytis fabae, Fusarium oxysporan and Candida albicans. On the other hand the synthesized compounds were also screened for their anti tubercular activity. The results revealed that some of these compounds have shown promising antimicrobial and antitubercular activity in comparison with standard drugs.

Dhameliya et al¹³., Synthesised a series of (Z) –n-(5-Benzylidene-4-oxo-2 substituted phenylthiazolidin-3-yl)-5-((1, 3-dioxoisoindolin-2-yl)methyl)-2-hydroxybenzamide derivatives.

All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities.

Chandra Kant Belwal et al¹⁴., synthesised novel series of thiazolidinone derivatives of 4-(4-oxo-2-phenylthiazolidin-3-yl) benzoic acid. The synthesized compounds were screened for their antifungal activity. Antifungal activity study of the synthesized thiazolidinone derivatives of 4-(4-oxo-2-phenylthiazolidin-3-yl) benzoic acid revealed that all compounds showed moderate activities against selected microbial strains.

Mukesh C. Patel et al¹⁵., synthesised a series of (Z) –N-(5-Benzylidene-4-Oxo-2-Substituted Phenylthiazolidin-3-yl)-5-((1, 3-dioxoisoindolin-2-yl)methyl)-2-hydroxybenzamide. All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities. In summary, preliminary results indicate that some of the newly synthesized title compounds exhibited promising antibacterial activities and they warrant more consideration as prospective antimicrobials.

P.M. Ronad et al¹⁶., Synthesis and antimicrobial activity of 7-(2-substitutedphenylthiazolidinyl)-benzopyran-2-one derivatives A series of 7-(2-substituted phenylthiazolidinyl) -benzopyran-2-one derivatives have been synthesized. Schiff bases and title compounds were evaluated for antibacterial and antifungal activities against various bacterial and fungal strains. The results showed that compounds 3d, 3f, 4d, 4f and 4i (100 mg/ml) exhibited good antibacterial and antifungal activity as that of standard antibiotics Ciprofloxacin and Griseofulvin.

Arun Singh et al¹⁷., synthesized a series of3-(2-(5-benzoyl-1H-benzo[d][1,2,3]imidazol-1-yl)acetyl)-2-alkylthiazolidin-4-one derivatives(5a-d). All the newly synthesized compounds were evaluated for their antibacterial and antifungal activities.

2. ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY:

Taranalli AD et al.,¹⁸ synthesized a series of thiazolidine-4-one derivatives from sulfanilamide and evaluated for anti-inflammatory, analgesic activity. Anti-inflammatory activity was investigated by carrageenan induced rat paw edema method and analgesic activity by acetic acid induced writhing and rat caudal immersion method. The anti-inflammatory, analgesic activity was performed in 100 mg/kg b.w. rats. The nimesulide was used as standard drug for comparison. The compound [IX] and compound [X] with substitution R'-CH3 showed potential activity.

Kumar et al.,¹⁹ synthesized a series of 3-[4'(p-chlorophenyl) thiazol-2'-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethy]-6- bromoquinazolin-4-ones and screened them for anti-inflammatory and analgesic activities. Compound [XI] was found to be most active in both the activities. They found that the presence of thiazolidinone ring have shown much better anti-inflammatory and analgesic activity at 50 mg/kg po as compared to their parent compounds.

Vaidya et al.,²⁰ synthesized a series of 4-thiazolidinone derivatives . The synthesized compounds were screened for anti-inflammatory activity. Among the entire test compounds, III have shown promising anti-inflammatory activity as compared to the rest. All the experimental results were statistically significant.

IIIa: R=4-SCH_3,R₂=4-OCH₃,R₃=H.

Anbalagan et al.,²¹synthesized a new series of 2-[(thiazolidin-4-one)-phenyl]-1H-Phenylbenzimidazoles.The synthesized compounds were tested for analgesic activity by writhing reflex method and anti-inflammatory activity by carrageenen induced paw edema method. The synthesized compounds have shown significant activity of analgesic and anti-inflammatory activity comparable to that of standard.

Sugumaran Murugesan et al.,²² a series of 4- thiazolidinone derivatives were synthesized from 4-amino benzoic acid. The two synthesized compounds SS5 and SS6 were screened for anti-inflammatory and analgesic activity. Anti-inflammatory activity was evaluated by carrageenan-induced paw edema test and analgesic activity by Eddy’s hot plate method. Both the compounds showed good activity. All the experimental results were statistically significant. The anti-inflammatory and analgesic activity confirmed that the test compound SS6 showed superior activity than SS5. However, the test compounds were found to be less active than the standard drugs used.

3.ANTI CANCER AND ANTI-PROLIFERATIVE ACTIVITY

Arun M. Isloor et al.,²³ Synthesised a new series of 2-(3-substituted-1H-pyrazol-4-yl)-3-(3-substituted-5-sulfanyl-1,2,4-triazol-4-yl)-1,3-thiazolidin-4-one (4a–o). The compounds exhibited dose-dependent cytotoxic effect in MTT assay in human breast cancer (MCF-7) cells. Apoptotic degradation of DNA due to action of potent thiazolidin-4-ones was analysed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay). A concentration-dependent increase in tail length and olive tail moment was observed when treated with thiazolidin-4-ones.

Gududuru et al.,²⁴ described the synthesis and biological evaluation of new 2-aryl-4-oxo-thiazoilidin-3-yl amides against prostate cancer cells. The antiproliferative effects of synthesized compounds were examined in five human prostate cancer cell lines (DU-145, PC- 3, LNCaP, PPC-1 and TSU). Three potent compounds have been identified (VI, VII and VIII), which are effective in killing prostate cancer cells with improved selectivity compared to serine amide phosphates (SAPs).

Gududuru et al.,²⁵ described the synthesis and biological evaluation against prostate cancer cells of new 2-aryl-4-oxo-thiazolidin-3-yl amides. The antiproliferative effects of synthesized compounds were examined in five human prostate cancer cell lines (DU-145, PC-3,LNCaP, PPC-1, and TSU). Three potent compounds have been detected (43, 44 and 45), which are effective in killing prostate cancer cells with improved selectivity compared to serine amide phosphates (SAPs) [37].The compound 46 was screened against nine types of human cancer cells and showed significant cytotoxic activity in the case of lung cancer, melanoma and renal cancer, where the reduction in growth was found to be 75%, 97% and 84%, respectively, at the concentration of 1.0 x 10-4M [38].

Bhushan M. Panchabunde et al.,²⁶ synthesized a series of new thiazolidin-4-ones by the reaction of different substituted acetophenones with thiourea in presence of propanol to give 2-amino-4-aryl thiazol (1) which react with chloroacetyl chloride to produce the corresponding 2-chloro acetamido-4-arylthiazoles (2).The latter was treated with potassium thiocyanate in refluxing acetone to afford the related 2-imino-3-(-4-aryl thiazol-2-yl)-thiazolidin-4-ones (3).The synthesized compounds showed significant inhibition of cell by in-vitro method using MTT assay.

4. ANTI VIRAL ACTIVITY

A. ANTI HIV ACTIVITY

Jan Balzarini et al.,²⁷ synthesized a series of novel thiazolidin-4-ones bearing a lipophilic adamantyl substituent at position 2, and versatile substituent’s on the nitrogen atom of the thiazolidine ring, the compound (+)-2- adamantan-1-yl-3-(4,6-dimethyl-pyridin-2-yl)- thiazolidin-4-one [XIV] was endowed with a remarkable antiviral potency (EC50 ¼ 0.35 mM). The adamantane moiety played an important role in the eventual antiviral activity of the compound. This compound behaved as a typical non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI) with non-competitive inhibition against RT with respect to the substrate(ki1/4 12 mM).

The anti-HIV activity of several series of 2, 3- diaryl-1, 3-thiazolidin-4-ones [XV] has been studied by Chavan, Y.B. et al.,^28,29,30 Which are reported as a new family of antiviral agents acting as NNRTIs with minimal cytotoxicity.

B. ANTI RETROVIRAL ACTIVITY

There are several works in the literature describing the thiazolidinones highly active as non-nucleoside reverse transcriptase inhibitor(NNRTI) with minimal cytotoxicity. The biological activity of 1,3-thiazolidin-4-ones is associated with the ability to assume a conformation “butterfly-like” shape. From the SAR point of view, the anti-HIV activity is strongly influenced by the nature of the substituent at 2 and 3 position of the thiazolinone nucleus. The presence of the two halogen atoms at 2 and 6 position restricted the rotation of the phenyl ring (at 2-position on thiazolidinone ring) and allowed the molecules to assume the characteristic butterfly-like conformation.

The rings 2-pyridinyl and 2-pyrimidinyl attached at N-3 atom enhances the HIV activity. The replacement of these heterocycles for a phenyl [25], a furfuryl [26], a thiazol or a thiadiazol [27], moiety reduce the HIV-RT inhibitory activity. The replacement of the carbonyl group with the isostere thiocarbonyl group negatively influences the activity with appreciably decreases [28].

C. ANTI YELLOWFEVER VIRUS ACTIVITY

Sriram et al.,³¹ described the synthesis of 1,3-thiazolidin-4-ones bearing diaryl ring at C-2 and N-3 positions. The compounds were evaluated for their inhibitory effects on the replication on yellow fever virus in green monkey kidney, by means of a cytopathic effect reduction assay. Among these compounds, the 2-(4-chlorophenyl)-3-(4-fluorophenyl)-1,3-thiazolidin-4-one (40) emerged as the most promissory anti-yellow fever virus agent with EC50 of 6.9 μM and CC50 more than 100 μM making it more potent than standard ribavirin.

5. ANTI DIARRHOEAL ACTIVITY

Several 1,3-thiazolidin-4-ones were synthesized and screened for antidiarrhoeal activity in mice. Although the results showed that the compounds were 15- to 80-fold less active than the reference loperamide, they were much less toxic, ≥ 1000 mg/Kg and 108.8 mg/Kg, respectively. The most active compound was the 2-phenyl-3-{2-[(4-phenyl-4-cyano)piperidino]ethyl}-1,3-thiazolidin-4-one (39).

6. ANTI- ARRYTHMIC ACTIVITY

Atrial flutter and atrial fibrillation are the most common cardiac arrhythmias and they are associated with an increase in heart failure, stroke, and mortality. Blockade of the Kv1.5 ion channel is potentially atrial-selective avenue for the treatment of atrial fibrillation and atrial flutter. Jackson et al.,³² described the synthesis and biological evaluation of thiazolidinone-based blockers of Kv1.5. The 3,4-dimethyl derivatives 41 (IC50 = 0.069μM) and 42 (IC50 = 0.270μM) were the most potent compounds of this series .

6. ANTI CONVULSANT ACTIVITY

Amin et al.,³³ reported some new substituted coumarinyl thiazolines, coumarinyl thiazolidin-4-ones and substituted chromenothiazoles and evaluated for the anticonvulsant activity. Compounds [XVII] and [XVIII] were the most active against PTZ induced seizures.

Wilson Cunico et al.,have been synthesized Several 5-[(2-phenyl-4-oxo-thiazolidin-3-yl) amino]-2-oxo-thio barbituric acids derivatives [XIX and XX]³⁴ and 3-({4-[2-alkylphenyl)-4- oxo-1,3-thiazolidin-3-yl]-1,3,4-thiadiazol-2-yl}methylamino)-2-methyl-6monosubstituted-quinazolin-4(3H)-one derivatives [XXI]³⁵ and screened in-vivo for their anticonvulsant activity.

P. Jaya Preethi et al.,³⁶synthesized a series of 4-thiazolidinones and 2-azetidinone derivatives by refluxing Schiff bases with different aromatic aldehydes. Schiff bases were synthesized by reaction of nicotinamide with hydrazine hydrate. The chemical structures of the synthesized compounds were confirmed by means of IR, 1H-NMR, mass spectroscopy and elemental analysis. Compound IIIa, IIId, IVa and IVd exhibited good Anti-convulsant activity.

Velmurugan. V et al.,³⁷synthesized Thiazolidinone derivatives from thiourea. The syntesized Thiazolidinone derivatives was undertaken to investigate the anticonvulsant activity by using maximal electroshock-induced seizure (MES) in mice. All the compounds were evaluated for their anticonvulsant activity by maximal electroshock seizure (MES) method. Some of the compounds showed more activity than the standard and some are equally active to standard drug phenytoin.

7. ANTIOXIDANT ACTIVITY

Shih et al.,³⁸ synthesized a series of sydnonyl substituted thiazolidinone and thiazoline derivatives and evaluated for their antioxidant activity. The antioxidant activity of compound [XXII] have been found to exhibit the significant DPPH (1, 1-diphenyl-2- picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E.

Arun M. Isloor et al.,³⁹Synthesised a new series of 2-(3-substituted-1H-pyrazol-4-yl)-3-(3-substituted-5-sulfanyl-1,2,4-triazol-4-yl)-1,3-thiazolidin-4-one (4a–o) by cyclo-condensation reaction of 5-substituted-4-[(3-substituted-1H-pyrazol-4ylmethylidene)amino]-2H-1,2,4-triazole-3-thione (3a–o) and thioglycolic acid. The synthesized compounds were screened for anti-oxidant activity. In vitro antioxidant studies like DPPH and ABTS-free radical scavenging assays-indicated moderate activity of thiazolidin-4-ones.

8. ANTI MALARIAL ACTIVITY

Solomon et al.,⁴⁰ reported the synthesis of chloroquine analogues having a 1, 3- thiazolidin-4-one nucleus at the terminal side chain amino group of 4-aminoquinoline [XVI]. All compounds were evaluated for their antimalarial activity against P. falciparum in-vitro and some compounds that have shown their activity comparable to standard drug were also evaluated against P. yoelli in-vivo. The best compound (IC50 = 0.039μM) posses superior in-vitro activity compared to chloroquine.

CONCLUSION:

In this article, we reviewed the literature data of biological activities of thiazolidinone. The thiazolidinone is not only synthetically important scaffold but also possesses a wide range of promising biological activities. Some thiazolidinone derivatives have better activity than standard drugs and could become a new drug for the market in future. In thiazolidinone substitution at nitrogen yielded potent compounds with good pharmacological activities.

FUTURE ASPECT:

Future Research and investigation could give some interesting results on substitution at various position of

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Received on 14.06.2013 Modified on 24.06.2013

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