SYNTHESIS AND ANTITUBERCULAR ACTIVITY OF 4-OXO-THIAZOLIDINE DERIVATIVES OF 2-AMINO-5-NITROTHIAZOLE

New series of N-[3-(2-amino-5-nitrothiazolyl)-propyl]-2-(substituted phenyl)-4-oxo-5(substituted benzylidene)-1,3-thiazolidine-carboxamide, 5(a-j) have been synthesized from 2-amino-5nitrothiazole as a starting material. The structure of all the synthesized compounds were confirmed by chemical and spectral analyses such as IR, H NMR, C NMR and FAB-Mass. All the final synthesized compounds 5(a-j) were screened for their antibacterial and antifungal activities against some selected bacteria and fungi with their MIC values and antitubercular activity screened against M. tuberculosis.


INTRODUCTION
Molecules containing thiazole ring systems are widely studied because of its low toxicity.Thiazole moiety is the key pharmacophore for the synthesis of several biological important molecules.Thiazole containing derivatives plays an important role in biological activity of many compounds such as antimicrobial activity [1,2], anti-inflammatory [3], antitumor activities [4], antiarrhythmic and anticoagulant activities [5].We also knows that imine derivatives possess potent activities including antibacterial [6,7], antifungal [8,9] and antitubercular [10] activities.Thiazolidine-4-ones are an important subunit of heterocyclic compounds having valuable biological activities.The thiazolidinones and correlated motifs have high biological relevance since the discovery.They are present in both natural products and pharmaceutical compounds.Some synthesized thiazolidinone derivatives possess antimicrobial [11][12][13][14], antidiabetic agents [15], antiviral [16], anti-inflammatory [17] activities.
In the present study, we have synthesized new series of biologically active thiazolidine derivatives.We have described the synthesis of a new series of N- [3-(2-amino-5-nitrothiazolyl)propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide, compounds 5(a-j) and other intermediate of the series compound 1, 2, 3(a-j), 4(a-j) (Scheme 1).The structure of all the synthesized compounds were confirmed by chemical and spectral analyses such as IR, 1 H NMR, 13 C NMR and FAB-Mass.All the final synthesized compounds 5(a-j) were screened for their antibacterial and antifungal activities against some selected bacteria and fungi with their MIC values and antitubercular activity screened against M. tuberculosis.

Biological significance
The results of the all described activities (antibacterial, antifungal and antitubercular) are summarized in Tables 1.The results of the antimicrobial screening data revealed that all final compounds of the series compounds 5(a-j) showed considerable and varied activity against the selected microorganism.A new series of N- [3-(2-amino-5-nitrothiazolyl)-propyl]-2-(substituted phenyl)-4-oxo-5-(substituted benzylidene)-1,3-thiazolidine-carboxamide, compounds 5(a-j) were synthesized and screened for their antimicrobial and antitubercular activities data (as shown in Table 1) revealed that all the synthesized compounds 5(a-j) have a structure activity relationship (SAR) because activities of compounds varies with substitution.Nitro group containing compounds (5h, 5i and 5j) showed higher activity than chloro (5c, 5d) and bromo group containing compounds (5e, 5f).On the basis of SAR, we concluded that the sequence of the activity is following NO 2 > Cl > Br > H The investigation of antimicrobial (antibacterial, antifungal and antitubercular) data revealed that the compounds (5c), (5d), (5e), (5f), (5h), (5i) and (5j) displayed high activity in the series, the compounds (5b) and (5g) showed moderate activity and rest compounds showed less activity against all the strains compared with standard drugs.The MIC values of standard streptomycin for all bacterial strain and griseofulvin for all fungal strain were in the range of 2.50-3.25 and 6.25-12.50µg/mL, respectively.Isoniazid and rifampicin were used as standards, MIC values in the range of 1.25-2.50µg/mL for M. tuberculosis.

EXPERIMENTAL
Melting points were taken in open capillaries and are uncorrected.Progress of reaction was monitored by silica gel-G coated TLC plates in MeOH:CHCl 3 system (1:9).The spot was visualized by exposing dry plate in iodine vapours.IR spectra were recorded in KBr disc on a Schimadzu 8201 PC FTIR spectrophotometer (ν max in cm -1 ) and 1 H and 13 C NMR spectra were measured on a Brucker DRX-300 spectrometer in CDCl 3 at 300 and 75 MHz respectively using TMS as an internal standard.All chemical shifts were reported on δ scales.The FAB mass spectra were recorded on a Jeol SX-102 mass spectrometer.Elemental analyses were performed on a Carlo Erba-1108 analyzer.The analytical data of all the compounds were highly satisfactory.For column chromatographic purification of the products, Merck silica Gel 60 (230-400 Mesh) was used.The reagent grade chemicals were purchased from the commercial sources and further purified before use.

Synthesis of 1-(3-chloropropyl)-2-amino-5-nitrothiazole, compound 1
2-Amino-5-nitrothiazole (0.345 mol) and 1-bromo-3-chloropropane (0.345 mol) in methanol (100 mL) were stirred on a magnetic stirrer for about 6.5 h at room temperature.The completion of the reaction was monitored by silica gel-G coated TLC plates.After the completion of the reaction the product was filtered and purified over a silica gel packed column chromatography using CHCl 3 :CH 3 OH (8:2 v/v) system as eluant (120 mL).The purified product was dried under vacuo and recrystallized from ethanol at room temperature to yield compound 1 (Figure 1).

Synthesis of N-[3-(2-amino-5-nitrothiazolyl)-propyl]-urea, compound 2
Compound 1 (0.2256 mol) and urea (0.2256 mol) in methanol (100 mL) were stirred on a magnetic stirrer for about 6.5 h at room temperature.The completion of the reaction was monitored by silica gel-G coated TLC plates.After the completion of the reaction the product was filtered and purified over a silica gel packed column chromatography using CHCl 3 :CH 3 OH (8:2 v/v) system as eluent (120 mL).The purified product was dried under vacuo and recrystallized from ethanol at room temperature to yield compound 2 (Figure 2).

Synthesis of N-[3-(1H-2-amino-5-nitrothiazolyl)-propyl]-N'-[(phenyl)-methyli dene]-urea, compound 3a
Compound 2 (0.0330 mol) and benzaldehyde (0.0330 mol) in methanol (100 mL) in the presence of 2-4 drops of glacial acetic acid were first stirred on a magnetic stirrer for about 2 h followed by reflux on a steam bath for about 3.5 h.The completion of the reaction was monitored by silica gel-G coated TLC plates.The product was filtered and cooled at room temperature.The filtered product was purified over a silica gel packed column chromatography using CH 3 OH:CHCl 3 (7:3 v/v) as eluent (75 mL).The purified product was dried under vacuo and recrystallized from ethanol at room temperature to furnish compound 3a (Figure 3).Compounds 3 (b-j) have also been synthesized by using similar method as above.

Synthesis of N-[3-(2-amino-5-nitrothiazolyl)-propyl]-2-(phenyl)-4-oxo-1,3-thiazolidinecarboxamide, compound 4a
The compound 3a (0.015 mol) and thioglycolic acid (0.015 mol) in methanol (50 mL) in the presence of ZnCl 2 (0.015 mol) were allowed to react at room temperature.The reaction mixture was first stirred on a magnetic stirrer for about 2 h followed by reflux on a steam bath for about 4 h.The product was filtered and cooled at room temperature.The completion of the reaction was monitored by silica gel-G coated TLC plates.The filtered product was purified over a silica gel packed column chromatography using CH 3 OH:CHCl 3 (7:3 v/v) as eluent (80 mL).The purified product was dried under vacuo and recrystallized from ethanol at room temperature to furnish compound 4a (Figure 4).Compounds 4 (b-j) have also been synthesized by using similar method as above.
Compounds 5 (b-j) have also been synthesized by using similar method as above.