Rational Substitution-Driven Enhancement of Anti-Mycobacterium tuberculosis Activity in a Quinoline-Isonicotinic Acid...

The obstinatproblem of drug resistance in tuberculosis (TB) requires sustained efforts in the search for new drug molecules. Building on our previously developed synthetic hybrid compound, UH-NIP-16, which demonstrated anti-Mycobacterium tuberculosis (M.tb) activity, we synthesized and evaluated 15 new derivatives to improve its potency. Among these, two lead compounds, UN-7 and UN-14, bearing hydrogen and methyl substitutions at the sixth position, respectively, along with a 2-phenoxy moiety, exhibited a ∼5-fold reduction in MIC50 values across laboratory, clinical, and multidrug-resistant M.tb strains relative to UH-NIP-16. Both compounds displayed a bacteriostatic mechanism of action and exhibited predominantly additive or indifferent interaction profiles in combinatorial antitubercular studies. Importantly, UN-7 and UN-14 showed minimal cytotoxicity toward mammalian cells and effectively reduced intracellular bacterial burden in an in vitro infection model. A coupled enzymatic assay revealed that UN-7 and UN-14 inhibited mycobacterial shikimate kinase (Mt-SK) activity by approximately 65%, a target not inhibited by the parent compound UH-NIP-16. In silico ADMET analyses indicated several favorable drug-likeness properties despite predicted liabilities, including Ames mutagenicity and low aqueous solubility. Collectively, these findings identify UN-7 and UN-14 as structure-activity relationship (SAR)-guided derivatives of the UH-NIP-16 scaffold with improved antimycobacterial activity and promising potential for further antitubercular lead development.