Design And Synthesis Of Disubstituted Thiazolyl Schiff-Bases As Novel Β-Lactamase Inhibitors

Abstract

An interesting molecular framework comprising of schiff-base linked disubstituted thiazoles (G1-G6) was designed to develop safe and efficacious antimicrobial agents as β-lactamase inhibitors. A series of compounds was synthesized via reaction of substituted ethanones with thiosemicarbazide followed by α-haloketones to obtain the desired products. The structure of the synthesized compounds was elucidated by physiochemical and spectral techniques including IR, Mass, ¹H-NMR and ¹³C NMR. Similarly, chemical shift values in NMR spectra were found corresponding to the proposed structure. In-silico study was conducted for the binding affinity with the target protein β-lactamase (PDB ID:3UDI). The binding mode of this class of compounds, showing crucial hydrogen bonds and pi–pi stacking interactions with the key amino acid residues Cys47, Arg469, and Tyr323 at the active site of β-lactamase, was assessed by molecular docking studies. The synthesized compounds were screened for their in-vitro antibacterial activity against the gram-positive bacteria Bacillus subtilis (MTCC 441), Staphylococcus aureus (MTCC 1430), Micrococcus luteus (MTCC 1538) and gram-negative bacteria Klebsiella pnuemoniae (MTCC 432), Escherichia coli (MTCC 1573), Pseudomonas aeruginosa (MTCC 424), and Psedomonas fluorescens (MTCC 2421) using clavulanic acid as the standard. The compounds (G2, G4 and G5) were potentially effective in inhibiting the Gram-positive as well as Gram-negative bacteria. The preliminary screening revealed that these thiazole analogues could be developed into potential β-lactamase inhibitors.