An approach to design, in silico predictions and molecular docking studies of 1,3,4-oxadiazolyl sulphonamides as possible inhibitors of bacterial Mur enzymes, the amino acid ligases in peptidoglycan synthesis

Abstract

The extensive use of antibiotics in hospitals and community since their introduction into medical practice has created major evolutionary pressures in bacteria to develop various resistance mechanisms. This phenomenon has led to increased morbidity, mortality and health care costs. The search for new antibacterial agents directed towards novel targets became highly imperative. The biosynthetic pathway of cytoplasmic peptidoglycan precursor is currently gaining much interest as a target site for antibacterial therapy. Since the mid-1990s, many inhibitors of the Mur cytoplasmic enzymes have been reported, but none has yet led to the development of a clinically utilized therapeutic agent. In view of the potentiality of sulphonamide and 1,3,4-oxadiazole moieties, it was planned to incorporate both the scaffolds. Thus a series of 4-Amino-N-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl] substituted benzene-1-sulfonamides (1-10) were designed, predicted for molecular properties and docking studies were conducted on Mur enzymes. The presence of the two pharmacophoric scaffolds, oxadiazole and sulphonamide influenced the good bioactive scores. Docking studies further supported the biological activities. The results indicated the possible inhibitory activity towards the Mur enzymes. The results also indicate the selectivity towards Mur A, Mur C, & Mur E enzymes. Of all the compounds, compound 6 and compound 9 with isopropyl substitution exhibited the highest scores against all the three Mur enzymes. Compound 7 showed good binding interactions with Mur C and Mur E.