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

Authors :
da Silva FF
Paz JD
Rambo RS
Gonçalves GA
Muniz MN
de Matos Czeczot A
Perelló MA
Berger A
González LC
Duarte LS
da Silva AB
Ferreira CAS
de Oliveira SD
Moura S
Bizarro CV
Basso LA
Machado P
Source :
Journal of medicinal chemistry [J Med Chem] 2024 Dec 26; Vol. 67 (24), pp. 21781-21794. Date of Electronic Publication: 2024 Dec 04.
Publication Year :
2024

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 bc <subscript>1</subscript> 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 <subscript>0- t </subscript> 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.

Details

Language :
English
ISSN :
1520-4804
Volume :
67
Issue :
24
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
39630172
Full Text :
https://doi.org/10.1021/acs.jmedchem.4c01302