Keeping Up with the Q’s: Mechanistic Insights and Validation of Quinoline and Quinazoline Scaffolds as Potent Drugs against Tuberculosis

The eternal battle against Tuberculosis necessitates the discovery of novel drugs. This study outlines identification of novel quinoline and quinazoline series through phenotypic screening of the ChemDiv library against Mtb-H37Rv. The potency, mode of inhibition, and structure–activity relationships around the confirmed actives are described. Both series disclosed potent anti-TB activity against drug-sensitive and drug-resistant strains. The quinazoline series exhibited cytotoxicity toward eukaryotic cells, while the quinoline compounds were both active and noncytotoxic. Among the quinoline compounds, the most promising molecule, IIIM-IDD-Q1b, exhibited an IC90 of 9.7 μg/mL, with no observed cytotoxicity, resulting in a high safety index (>10). It demonstrated potent intracellular inhibition against Mtb as made evident by fluorescence imaging and CFU enumeration. Mode-of-action studies revealed that quinoline compounds target DNA gyrase, while quinazoline series target ATP synthase. Overall, both series demonstrate promising biological properties and a favorable pharmacokinetic profile. Further medicinal chemistry optimization could enhance and boost the anti-TB potency of the identified compounds.