Design and Evaluation of Quinoline-Schiff Bases Targeting Mtb DNA Gyrase: In Vitro and Computational Approaches.

A new series of quinoline-Schiff bases was designed and synthesized using a straightforward and efficient methodology involving the condensation of 2-chloroquinoline-3-carbaldehyde with substituted aromatic amines. A total of 17 quinoline-Schiff bases were synthesized with 56%-86% yields and characterized by using 1H NMR, 13C NMR, and high-resolution mass spectra (HRMS) as potent anti-mycobacterial agents with Mtb DNA gyrase inhibitory activity. Among all, compound 7f displayed a significantly potent broad-spectrum antitubercular and antimicrobial activity against most of the tested strains of bacteria and fungi, with minimum inhibitory concentration (MIC) values in the range of 1.95-15.62 µg/mL. Seven quinoline-Schiff bases (7a, 7b, 7d, 7g, 7o, 7p, and 7q) displayed a key improvement in both drug-sensitive and drug-resistant strains with MIC range of 3.90-15.62 µg/mL, respectively. A subsequent in vitro study evaluated the most promising compounds (7a, 7d, 7f, 7p, and 7q) against Mtb DNA gyrase. Among these, compounds 7a, 7d, and 7f exhibited the highest activity, with IC50 values of 1.98, 1.26, and 3.96 µM, respectively. Molecular docking studies revealed strong binding affinities of the synthesized derivatives with the Mtb DNA gyrase enzyme, highlighting key hydrogen and carbon-hydrogen bond interactions with Tyr21, Gly84, Asn85, Asp110, Gln125, and pi-pi and pi-alkyl interactions with Arg62, Phe116, Pro118, Ala146, and Val147. Furthermore, ADMET profiling of the most effective derivatives 7a, 7d, and 7f demonstrated comparable bioavailability scores (0.55) with varied lipophilicity (MLOGP: 2.90-3.39) and lower TPSA compared to ciprofloxacin (CFX). These comprehensive analyses and properties suggest favorable drug-likeness with potential for further optimization.