Synthesis and antibacterial studies of 2-aryl-3-alkanamido-4H-thiazolidin-4-one derivatives

1 Introduction

Infectious diseases are one of the major health problems of the world population. Certainly, the rapid development of resistance to the existing antimicrobial drugs is the root cause of this global issue. This opens the gate for the medicinal chemists for the development of novel antimicrobial drugs having a different mechanism of action to combat the problem of multi-drug resistance (Wise, 2008; Coleman, 2004; Cassell and Mekalanos, 2001). In a wide variety of heterocyclic structures, the thiazolidin-4-one nucleus constitutes an important class displaying a broad spectrum of biological activities (Verma and Saraf, 2008). Thiazolidin-4-one ring also found in naturally occurring actithiazic acid [(−) 2-(5-carboxypentyl) (thiazolidin-4-one)] which has been isolated from Streptomyces strains and exhibited highly specific in vitro activity against Mycobacterium tuberculosis (Sobin, 1952). Thiazolidin-4-one derivatives have been reported to possess diverse biological activities, such as antimicrobial (Ozkirimli et al., 2009; Mulwad et al., 2009; Saeed et al., 2007; Vicini et al., 2006; Kavitha et al., 2006; Mishra et al., 1999), anti-inflammatory (Sharma et al., in press; Deep et al., 2010), anti-HIV (Rao et al., 2004), anticancer (Guzel et al., 2006), anticonvulsant (Ragab et al., 1997), etc. It has been found that thiazolidin-4-one nucleus inhibits the bacterial enzyme MurB, a key enzyme responsible for the biosynthesis of peptidoglycan (Andres et al., 2000). Further, derivatives of long chain fatty acid hydrazides have been reported to possess the biological activity (Rauf et al., 2008; Awasthi et al., 2007). These reports including our ongoing research program in the field of synthesis and antimicrobial activity of medicinally important compounds (Deep et al., 2014; Kumar et al., 2011) inspired us to undertake the synthesis of some thiazolidin-4-ones as the novel derivatives of long chain fatty acid hydrazides. The synthesized compounds were characterized on the basis of elemental analysis, IR, ¹H NMR and Mass spectral data. All the compounds were screened for their in vitro antibacterial activity.

2 Results and discussion

2.1

2.1 Chemistry

The syntheses of 2-aryl-3-alkanamido-4H-thiazolidin-4-ones were achieved following the steps outlined in Scheme 1. Alkanoic acid hydrazides 1 were prepared by the reaction of hydrazine hydrate with the corresponding methyl esters of the acids. The hydrazides 1 then on refluxing with aromatic aldehydes and 2–3 drops of glacial acid in methanol furnished alkanoic acid hydrazones 2. Thioglycolic acid reacted with 2 in the presence of anhydrous zinc chloride to give 3. All the compounds were obtained in good yield. These compounds were characterized on the basis of elemental and spectral analyses. IR spectra of each compound showed a band for N–H stretching vibrations near 3340 cm⁻¹. The C⚌O stretching vibrations of amide I band were observed in the range of 1636–1650 cm⁻¹ while the amide II, i.e., N–H bending vibrations displayed a band at about 1550–1557 cm⁻¹. The C–H stretching vibrations for alkyl chain were observed in the range of 2916–2919 cm⁻¹ whereas bending vibrations for methylene scissoring were observed constantly at 1465 cm⁻¹_. The characteristic methylene rocking vibrations of the long alkyl chain was observed at 720 cm⁻¹.The absorption for aromatic C–H bending vibrations was observed below 900 cm⁻¹. In case of ¹H NMR, the chemical shift value for the N–H group was observed in the range of 8.18–8.15 δ (ppm) and appeared as singlet (s). Aromatic protons appeared as multiplet (m) in the assigned value of 7.99–6.75 δ (ppm). The methine proton (S–CH–N) and the methylene protons (S–CH₂–C) of the thiazolidinone nucleus absorbed at 5.98–5.92 δ (ppm) and 2.76–2.71 δ (ppm), respectively, and appeared as singlets. The methylene protons alpha to the C⚌O group [CO–CH₂–CH₂–(CH₂)_n–CH₃] appeared as triplet in the range of 2.28–2.22 δ (ppm) whereas the methylene protons beta to the C⚌O group [CO–CH₂–CH₂–(CH₂)_n–CH₃] were observed at 1.73–1.67 δ (ppm) and appeared as multiplet. The multiplet was also observed at 1.39–1.22 δ (ppm) for the several methylene groups of the long fatty acyl chain [CO–CH₂–CH₂–(CH₂)_n–CH₃]. The methyl group of the long fatty acyl chain appeared as triplet at 0.89–0.85 δ (ppm). All the title compounds showed [M+H]⁺ of 100% intensity as the molecular ion peak along with isotopic peak at [M+2+H]⁺ of about 4% intensity of the parent ion peak due to the presence of sulfur atom. Compounds containing chlorine showed isotopic peak of about 35% intensity whereas the bromo compounds exhibited isotopic peak of about equal intensity. The results of elemental analyses were found in good agreement with the calculated values.

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Scheme 1

Synthesis of 2-aryl-3-alkanamido-4H-thiazolidin-4-ones.

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3 Experimental

4 Conclusion

Present study describes the synthesis of a series of 2-aryl-3-alkanamido-4H-thiazolidin-4-ones starting from the hydrazides of the long chain fatty acids. The compounds were characterized by modern analytical techniques, such as CHN analyses, IR, Mass and proton NMR spectra. All the title compounds were screened for their in vitro antibacterial activity against B. subtilis, S. aureus (Gram positive) and E. coli, P. aeruginosa (Gram negative) and their minimum inhibitory concentration (MIC) were determined. The results of antibacterial activity showed that compounds containing electron withdrawing groups, e.g., chloro, bromo, fluoro or nitro were found to be more active than the compounds containing electron releasing groups such as methyl, methoxyl or hydroxyl. These results suggest that some more compounds using different aromatic or hetero-aromatic aldehydes and fatty acids should be synthesized and screened for their antibacterial activity to explore the possibility of 2-aryl-3-alkanamido-4H-thiazolidin-4-ones as a novel series of antibacterials.