Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites

•The full synthesis of compound 1771 was reported.•Compound 1771 was found to have a good binding mode with LtaS active site reinforcing the hypothesis that 1771 could act as inhibitor of this enzyme to block the synthesis of LTAs.•Three main metabolites were identified upon incubation of 1771 in mice serum (pH7.4) (half-life of 210 min).•The lack of antibacterial activity of the synthesized metabolites indicated that the biological activity is caused by the intact compound 1771 rather than its fragments. Amongst drug resistant Gram-positive bacteria, Staphylococcus aureus is a pathogen of great concern as it is the leading cause of life-threatening nosocomial and community acquired infections which are often associated with implanted medical devices. The biosynthesis of lipotheicoic acid (LTA) by S. aureus has been recognized as a promising antibacterial target, owing its critical role in the growth and survival of Gram-positive bacteria. Here we report for the first time the chemical synthesis and characterisation of an oxadiazole based compound (1771), previously described as an inhibitor of LTA biosynthesis by targeting Lta synthase enzyme (LtaS). To investigate its controversial mode of action, we also performed molecular docking studies, which indicated that 1771 behaves as a competitive inhibitor against LtaS. We also synthesised and evaluated the antimicrobial activity of 1771 metabolites which we have identified from its decomposition in mouse serum, proving that the biological activity was caused by intact 1771. [Display omitted]