Unveiling the Antimycobacterial Potential of Novel 4-Alkoxyquinolines: Insights into Selectivity, Mechanism of Action, and In Vivo Exposure

Abstract

This work presents a comprehensive investigation into the design, synthesis, and evaluation of a novel series of 4-alkoxyquinolines as potential antimycobacterial agents. The design approach, which combined molecular simplification and chain extension, resulted in compounds with potent and selective activity against both drug-susceptible and multidrug-resistant Mycobacterium tuberculosis strains. The lead molecule, targeting the cytochrome bc₁ complex, exhibited favorable kinetic solubility and remarkable chemical stability under acidic conditions. Despite in vitro ADME evaluations showing low permeability and high metabolism in rat microsomes, the lead compound exhibited bacteriostatic activity in a murine macrophage model of TB infection and demonstrated promising in vivo exposure following gavage in mice, with an AUC_0-t of 127.5 ± 5.7 μM h. To the best of our knowledge, for the first time, a simplified structure from 2-(quinolin-4-yloxy)acetamides has shown such potential. These findings suggest a new avenue for exploring this chemical class as a source of antituberculosis drug candidates.

Figure 1

Scaffold evolution starting from 2-(quinolin-4-yloxy)acetamide 1, discovered through high-throughput screening, led to compounds 2 and 3, which showed optimized antimycobacterial activity. Molecules 4 and 5 were derived by molecular simplification of the amide function and exhibited a significant reduction in potency. Finally, the innovative design of 4-alkoxyquinolines, combining molecular simplification with chain extension explored in this study.

Scheme 1. Conditions: i = 1,3-Dibromopropane, Cs₂CO₃, NaI, CH₃CN, 25 °C, 24 h; ii = Anilines, K₂CO₃, NaI, toluene, 110 °C, 48-72 h

Yields were quantified after purification and were not optimized.