Coumarin-3-carboxamide derivatives as promising anti-tubercular agents: An In-silico and In-vitro approach

Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis that has continued to be a significant global health problem. The current study investigates novel coumarin-3-carboxamide derivatives as potential anti-tubercular agents against Mycobacterium tuberculosis . A library of 15 synthesized coumarin analogs was initially screened in-silico against three validated targets: Mycobacterial membrane protein large-3 (MmpL3), DNA Gyrase B ATPase (GyrB), and Enoyl acyl carrier protein reductase (InhA) using molecular docking. The stability of selected coumarin-protein complexes was assessed via 100 ns Molecular Dynamics (MD) simulations. Compounds were then evaluated in-vitro for activity against replicating (MABA) and non-replicating M. tuberculosis using the Low-Oxygen Recovery Assay (LORA). Molecular docking identified compounds 4i and 8 with comparable binding affinities and favourable interaction profiles relative to FDA-approved anti-TB drugs. MD simulations confirmed the stability of these complexes. In-vitro MABA screening showed moderate activity, with 4 g and 4 f achieving > 70 % inhibition at 10 μg/ml. Significantly, compound 4d demonstrated comparable activity against non-replicating M. tuberculosis in the LORA, exhibiting a lower MIC value (9.34 μM) than isoniazid (> 10 μM). The in-silico and in-vitro data suggest that the coumarin-3-carboxamide scaffold holds promise. Compounds 4i and 8 show strong target binding potential, while the selective activity of 4d against non-replicating bacilli is highly no for addressing latent or persistent TB infections. The moderate activity against replicating bacilli suggests room for optimization. Collectively, compounds 4i, 4 f, 8, and 4d represent potential coumarin-based scaffolds for developing therapeutics targeting both replicating and non-replicating M. tuberculosis .