Target-Based Antitubercular Drug Discovery: Scaffold Diversity and SAR Trends of Small Molecules Against Mycobacterium Tuberculosis

Abstract

Tuberculosis remains a major infectious disease, and the increasing incidence of multidrug-resistant Mycobacterium tuberculosis continues to limit current treatment options. This review summarizes recent medicinal chemistry efforts directed toward six important M. tuberculosis targets: InhA, DprE1, MmpL3, QcrB, DNA gyrase, and dihydrofolate reductase (DHFR). Emphasis is placed on the structural diversity and biological activity of potent molecules. SAR analysis relates changes in scaffold, substituent pattern, linker geometry, lipophilicity, and polarity to antimycobacterial potency and activity against resistant strains. Selected synthetic routes and clinically relevant antitubercular compounds are also discussed. Selected docking studies provide supportive structural information for representative potent inhibitors, while comparative SAR analysis provides an overview of the major structural features associated with activity across the target classes. Overall, the review summarizes recent medicinal chemistry advances in targeted antitubercular drug discovery and provides SAR considerations for further lead optimization.