Unveiling the\nAntimycobacterial Potential of Novel\n4‑Alkoxyquinolines: Insights into Selectivity, Mechanism of\nAction, and <i>In Vivo</i> Exposure

This work presents a comprehensive investigation into\nthe design,\nsynthesis, and evaluation of a novel series of 4-alkoxyquinolines\nas potential antimycobacterial agents. The design approach, which\ncombined molecular simplification and chain extension, resulted in\ncompounds with potent and selective activity against both drug-susceptible\nand multidrug-resistant Mycobacterium tuberculosis strains. The lead molecule, targeting the cytochrome <i>bc</i><sub>1</sub> complex, exhibited favorable kinetic solubility and\nremarkable chemical stability under acidic conditions. Despite <i>in vitro</i> ADME evaluations showing low permeability and high\nmetabolism in rat microsomes, the lead compound exhibited bacteriostatic\nactivity in a murine macrophage model of TB infection and demonstrated\npromising <i>in vivo</i> exposure following gavage in mice,\nwith an AUC<sub>0–<i>t</i></sub> of 127.5 ±\n5.7 μM h. To the best of our knowledge, for the first time,\na simplified structure from 2-(quinolin-4-yloxy)acetamides has shown\nsuch potential. These findings suggest a new avenue for exploring\nthis chemical class as a source of antituberculosis drug candidates.