Benzyl/phenyl-1,2,3-Triazole Tethered 3-Acetyl Coumarins as Potential Drug-Resistant Antitubercular Agents: Synthesis, Biology, and in Silico Investigations as Mtb DNA Gyrase Inhibitors

Abstract

Owing to the emergence of multi-drug resistant tuberculosis, there is a need for the exploration of new antitubercular agents. In this context, new coumarin-based 1,2,3-triazole hybrids were developed and evaluated for their antimicrobial activity against ESKAPE pathogens and the Mtb H37Rv strain. Among them, compounds 9 c and 12 showed MICs of 1 and 2 μg/mL, respectively, against the Mtb strain. The lead compounds exhibited a good selectivity index against Vero cells and were equally effective against ETB-resistant and RIF-resistant Mtb strains. Time-kill kinetic studies revealed the bacteriostatic properties of the lead compounds, while combination studies using FDA-approved antibiotics showed no drug interactions. Based on the structural similarity, it was envisaged that they might inhibit the DNA gyrase, which was further proved by the DNA supercoiling inhibition assay. Additionally, in silico docking studies, binding energy calculations, and ADME/T studies for the synthesized conjugates showed favourable pharmacokinetic and physicochemical characteristics. Hence, these molecules could further pave the way for discovering new potent antitubercular agents to combat AMR.