Design, synthesis and computational studies of new azaheterocyclic coumarin derivatives as anti-Mycobacterium tuberculosis agents targeting enoyl acyl carrier protein reductase (InhA).

In this study, we designed and synthesized a series of coumarin derivatives as antitubercular agents targeting the enoyl acyl carrier protein reductase (InhA) enzyme. Among the synthesized compounds, the tetrazole derivative 4c showed the most potent antitubercular effect with a minimum inhibitory concentration value (MIC) of 15 μg mL(-1) against Mtb H37Rv and could also inhibit the growth of the mutant strain (ΔkatG). Compound 4c was able to penetrate Mtb-infected human macrophages and suppress the intracellular growth of tubercle bacilli. Moreover, the target derivative 4c showed a potent inhibitory effect against InhA enzyme with an IC(50) value of 0.565 μM, which was superior to the reference InhA inhibitor triclosan. Molecular docking of compound 4c within the InhA active site revealed the importance of the 4-phenylcoumarin ring system and tetrazole moiety for activity. Finally, the physicochemical properties and pharmacokinetic parameters of 4c were investigated.