Synthesis and biological evaluation of 4-thiazolidinone derivatives as antitubercular and antimicrobial agents

1 Introduction

4-Thiazolidine derivatives are an important class of heterocyclic compounds known for their potential pharmaceutical applications. Recently, this framework containing compounds were effective against antimicrobial (Young et al., 2004), antischistosomal activity (Taha and Soliman, 2007), antifungal (Asati et al., 2005), antiinflammatory (Jain et al., 2006), antimalarial (Kristina et al., 2009), herbicidal (Sanemitsu et al., 2006), antiviral (Eiichi et al., 2007), antidiabetic (Murugan et al., 2009), and antioxidant (Shih and Ke, 2004) activities. Thiazole derivatives are heterocyclic compounds containing nitrogen and sulfur atoms in their structure and are proved to be clinically useful agents against different kinds of disease. Thiazole derivatives have been employed in the preparation of different important drugs required for treatment of antimicrobial (Gouda et al., 2010), antibacterial (Bharti et al., 2010; Khalil et al., 2009), antifungal (Bharti et al., 2010; Joshi and Srivastava, 2001), antiinflammatory (Giri et al., 2009), and antitubercular (Shiradkar et al., 2007), some of the thiazole derivatives are used as antiprotozoal (Ricardo et al., 2003) drugs. All above biological activities of thiazole and thiazolidine derivatives aroused our attention and promoted to synthesis a new series of N-[2-{2-(substitutedphenyl)-4-oxo-5-(substitutedbenzylidene)-1,3-thiazolidine}-iminoethyl]-2-amino-5-nitrothiazole, 5(a–m) by conventional and microwave methods. The structure of compounds 1, 2, 3(a–m), 4(a–m) and 5(a–m) were confirmed by IR, ¹H NMR, ¹³C NMR, FAB-Mass and chemical analysis. All the final synthesized compounds 5(a–m) were screened for their antimicrobial activity against some selected bacteria, fungi and antituberculosis study against M. tuberculosis. (Scheme 1)

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Scheme 1

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2 Materials and methods

3 Results and discussion

The reaction of 1-bromo-2-chloro-ethane with 2-amino-5-nitrothiazole was carried out in methanol to afford a product compound 1 The spectroscopic analyses of compound 1 showed absorption peaks for N—CH and C—Cl at 1382 and 740 cm⁻¹ in the IR spectrum. In the IR spectrum confirms the formation of compound 1. This fact was also supported by the disappearance of NH absorption of the 2-amino-5-nitrothiazole. The compound 1 on the reaction with hydrazine hydrate with continuous stirring at room temperature yielded compound 2. In the spectroscopic analyses of compound 2 we found two absorption peaks in IR spectrum for NH and NH₂ at 3370 and 3480 cm⁻¹ respectively while absorption of C—Cl has disappeared. This is clearly indicated that compound 1 gives the substitution reaction with hydrazine hydrate. This fact was also supported by ¹H and ¹³C NMR spectra because two signals appeared in the ¹H NMR spectrum for NH and NH₂ at δ 7.70 and δ 5.55 ppm respectively. All the facts together were strong evidence for the synthesis of compound 2. The compound 2 gave the condensation reaction with substituted benzaldehydes resulting in the production of Schiff bases N⚌CH, compound 3(a–m) which was confirmed by IR, ¹H NMR and ¹³C NMR spectra of compound 3(a–m). In the IR spectra an absorption was found in the range of 1549–1609 cm⁻¹ while a strong signal appeared in the range of δ 7.82–8.17 and δ 141.6–156.6 ppm in the ¹H NMR and ¹³C NMR spectra for N⚌CH of compound 3(a–m) respectively. The facts have also supported by the disappearance of the signal of NH₂ in the ¹H NMR spectra. The compound 3(a–m) on reaction with equimolar amount of thioglycolic acid in the presence of ZnCl₂ (act as a catalyst) in the trace amount gives the cycloaddition reaction and produced a five membered thiazolidinone ring, compound 4(a–m). The compound 4(a–m) showed a characteristic absorption for the cyclic carbonyl group in the range of 1738–1749 cm⁻¹ in the IR spectra. The ¹H NMR spectra aroused our attention and clearly indicate the presence of the two active methylene protons in the thiazolidine ring in the range of δ 3.10–3.46 ppm. The ¹³C NMR spectra of compound 4(a–m) also supported the fact that cyclic carbonyl group present and a signal appeared in the range of δ 168.7–177.9 ppm. All these facts were also supported by the two evidences that are (a) disappearance of N⚌CH proton and (b) appearance of N—CH proton in the range of δ 4.74–4.98 ppm in the ¹H NMR spectra of compound 4(a–m). The compound 4(a–m) underwent the Knoevenagel condensation reaction with substituted benzaldehydes in the presence of alkali metal alkoxide (C₂H₅ONa) to afford the compound 5(a–m). In the ¹H NMR spectra of the compound 5(a–m), we found the disappearance of two methylene protons of compound 5(a–m) and an appearance of a new signal for C⚌ CH in the range of δ 6.24–6.52 ppm in the ¹H NMR and two new signals for C⚌ CH and C⚌CH appeared in the range of δ 141.1–146.1 and δ 144.9–148.9 ppm in the ¹³C NMR spectra of the compound 5(a–m). These all above facts clearly confirmed the synthesis of all final products. All above compounds 1, 2, 3(a–m), 4(a–m) and 5(a–m) were also synthesized by microwave method. Characterization data were given in Table 1. All these above facts clearly confirmed the synthesis of all final products. Antimicrobial and antitubercular data (as shown in Tables 2 and 3) revealed that all the synthesized compound 5(a–m) have a structure activity relationship (SAR) because activity of compounds varies with substitution. Nitro group containing compounds (5h, 5i and 5j) showed higher activity than chloro (5c, 5d), or bromo group containing compounds (5e, 5f). Chloro and bromo derivatives also have higher activity than other rested compounds. On the basis of SAR, it was concluded that the activity of compounds depends on the electron withdrawing nature of the substituted groups. The sequence of the activity is following $${\text{NO}}_2>\text{Cl}>\text{Br}>{\text{OCH}}_3<\text{OH}>{\text{CH}}_3$$

4 Biological study

Series of newly synthesized compounds were highly active against selected microorganisms. The minimal inhibition values were determined using the filter paper disc diffusion method (Asati et al., 2005) and the concentrations have been used in ppm. All the final synthesized compounds 5(a–m) have dissolved in methanol and screened in vitro for their antibacterial activity against Bacillus subtilis, Escherichia coli and Staphylococcus aureus and antifungal activity against Aspergillus niger, Aspergillus flavus and Candida albicans. Standards for antibacterial and antifungal activity streptomycin and griseofulvin were used respectively. Standards also screened under the similar conditions for comparison. The antitubercular activity screened against the M. tuberculosis. For the antitubercular activity isoniazid and rifampicin were used as standard and also screened under the similar conditions.

5 Conclusion

Compound 1, 2, 3(a–m), 4(a–m) and 5(a–m) were synthesized by conventional and microwave methods, reaction time and yields of the synthesized compound displayed that the microwave method is more efficient than the conventional method. Compound 5(a–m) were screened for their antibacterial, antifungal and antitubercular activity against selected microorganisms. The investigation of antimicrobial data revealed that the compounds (5c), (5d), (5e), (5f), (5h), (5i) and (5j) displayed highly active in the series, compounds (5b), (5g) and (5m) showed moderate activity and rest compounds showed less activity against all the strains compared with standard drugs.