Novel series of 1,2,3-triazolyl-acetamide scaffolds: Synthesis, biological activity and computational molecular modeling

Abstract

A novel series of 1,2,3-triazolyl-acetamide derivatives 9 were synthesizsed starting from N-(2,4-difluoro-3-(methylthio)phenyl)but-3-ynamide and 2-azido-N-phenylacetamide. Structures of final compounds were confirmed by their 1H NMR, 13C NMR, IR, and mass spectral analysis. All new synthesised compounds were evaluated for their antibacterial activity against Gram (+ve) and Gram (–ve) microorganisms. Antibacterial activity of compounds 9h, 9c, 9d, and 9i (MICs = 4.0, 3.8, 3.2, 6.7 µg/mL) were the most potent inhibitory active against K. pneumoniae, S. aureus, S. pneumoniae, E. coli microorganisms respectively. We explored the probable key active site and binding mode interactions in carotenoid dehydrosqualene synthase from S. aureus complexed with bisphosphonate BPH-700 (2ZCS) protein and ligand 9i possesses highest hydrogen bonding amino acid interactions Ser21(2.86 Å, 3.16 Å), Lys17(2.91 Å), Lys20(2.76 Å), Lys17(2.13 Å), Ser21(1.87 Å). Scaffolds 9b, 9j and 9i exhibited highest potency with drug likeness score 0.84, 0.77 and 0.68 and processing Lipinski's rule of five as good oral bioavailability drugs.