Design, synthesis, and molecular modeling of novel thiazolopyridine-based inhibitors of enoyl acyl carrier protein reductase (InhA) as anti-Mycobacterium tuberculosis agents

Abstract

The updated guidelines from the World Health Organization highlight that treatment options for multidrug-resistant tuberculosis (MDR-TB) remain limited due to the scarcity of effective drugs. As a result, there is an urgent necessity to develop novel or repurposed drugs that demonstrate efficacy against multidrug-resistant (MDR) strains. In this study, a new series of thiazole-pyridine hybrids were thoughtfully designed and synthesized to assess their potential as antitubercular agents. These compounds were specifically created to target enoyl acyl carrier protein reductase (InhA), a crucial enzyme in the pathogenesis of Mycobacterium tuberculosis. The majority of the compounds evaluated demonstrated substantial antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 3.9 μg mL⁻¹ against Mycobacterium tuberculosis H37Rv. Among them, compound 5a was the most effective, with an MIC of 0.5 μg mL⁻¹. Further evaluations of compound 5a demonstrated its ability to disrupt bacterial biofilms and its strong inhibition of InhA, with an IC₅₀ of 0.19 ± 0.008 μg ml⁻¹, demonstrating superior efficacy compared to triclosan, which was employed as the reference drug. Molecular docking and dynamics analyses demonstrated that the pyridine ring and thiazole group are essential for binding affinity, and the pyridine-thiazole framework in compound 5a formed stable interactions within the active site of InhA.