4‑Aminoalkylquinolines as Potent Antitubercular Agents Targeting the Cytochrome bc₁ Complex

The development of new chemotypes active against drug-resistant Mycobacterium tuberculosis remains a major priority in tuberculosis drug discovery. Herein, a series of 4-aminoalkylquinolines was designed and synthesized to improve antimycobacterial potency and permeability. Structure-activity relationship studies identified key contributions of alkyl substitution at C-2 and hydrophobic terminal phenyl substituents. The most active derivatives exhibited submicromolar to low-nanomolar activity (MIC = 0.02-0.05 μM) and retained activity against multidrug-resistant clinical isolates. Evaluation against a QcrB_T313I strain indicated reduced susceptibility, consistent with inhibition of the cytochrome bc₁ complex. Single-crystal X-ray diffraction confirmed the structure of a representative compound. Selected molecules showed favorable selectivity in Vero and HepG2 cells and limited activity against non-mycobacterial bacteria. In vitro ADME profiling revealed pH-dependent solubility, good permeability, and rapid metabolic turnover. Zebrafish assays showed no detectable cardiac effects up to 0.3 μM. Overall, this chemotype represents a promising scaffold for antitubercular agents targeting mycobacterial respiration.