Molecular Hybridization of Naphthoquinones as Selective Inhibitors of Shikimate Kinase: A Promising Strategy Against Mycobacterium tuberculosis

Background: Tuberculosis (TB) remains a critical global health concern, exacerbated by the emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis. In the search for novel therapeutic agents, naphthoquinones have garnered interest due to their diverse mechanisms of action and potent antimycobacterial activity. In this study, we report the design, synthesis, and biological evaluation of a novel series of eleven naphthoquinone-based derivatives (compounds 22–32), developed through a molecular hybridization strategy targeting shikimate kinase (Mtb-SK) an essential enzyme present exclusively in M. tuberculosis. Methods: The compounds were synthesized via a straightforward and efficient synthetic route, and preliminary screening identified five molecules with significant anti-TB activity. Notably, compound 26, 4-(4-ethoxyphenyl) amino) Naphthalene-1,2-dione, exhibited a minimum inhibitory concentration (MIC) of 21.33 µM, comparable to ethambutol and substantially more potent than pyrazinamide. Results: Molecular docking studies indicated that all active compounds interact favorably within the shikimate binding pocket of Mtb-SK, following the proposed mechanism of action. Additionally, ongoing cytotoxicity assays in HepG2 cells aim to assess the selectivity of these derivatives. Conclusions: These findings support the potential of this new class of naphthoquinones as promising scaffolds for the development of anti-TB agents, contributing to the growing body of research focused on new chemotherapeutic options against tuberculosis.