Synthesis, Biological Evaluation and Molecular Modeling Studies of novel 2-[(2,4-dioxo-1,3-thiazolidin-3-yl)acetyl]-N-arylhydrazinecarbothioamides as Antibacterial Agents Targeting Alanine Racemase Enzyme

Abstract

Antibiotics play a prominent role in modern health care. Although, their role focuses on treatment of minor as well as serious infections, decreased antibiotic effectiveness has emerged as a major threat. Currently, the prime focus of researchers are to make structurally novel class of antibiotics with novel mechanism of action. The alanine racemase (AlaR) is a ubiquitous prokaryotic enzyme that provides peptidoglycan precursor D-alanine (D-Ala) for bacterial cell wall synthesis. The aim of present study is to identify some novel AlaR inhibitors with the ability to act as potent antibacterial agents. Herein we report five novel 2-[(2,4-dioxo,1,3-thiazolidin-3-yl)acetyl]-N-arylhydrazinecarbothioamides (5-9) which were synthesized and characterized by spectral data. All compounds were screened for their antibacterial activity and Geobacillus stearothermophilus alanine racemase enzyme (AlaR) inhibitory action. Compound 8 exhibited significant activity against the tested strains of bacteria when compared to the standard drug methicillin. In AlaR inhibition assay, the tested compound 8 showed maximum inhibitory activity (IC50 = 0.5 M) compared to the standard drug D-cycloserine (IC50 = 0.93 M) and inhibitor O-acetyl-L-serine (IC50 = 4.2 M). The in silico study showed that substitution of chlorine atom on the phenyl ring in case of compound 8 increased the hydrophobic interaction at the catalytic pocket resulting in high AlaR inhibitory action. The study suggests that the synthesized compound 8 can be considered as a promising antibacterial agent and a potent lead molecule for further antibacterial drug discovery and development.