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Unveiling the Antimycobacterial Potential of Novel 4-Alkoxyquinolines: Insights into Selectivity, Mechanism of Action, and In Vivo Exposure.
- 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.
- Subjects :
- Animals
Humans
Male
Mice
Rats
Drug Design
Macrophages drug effects
Macrophages metabolism
Structure-Activity Relationship
Tuberculosis drug therapy
Acetamides chemistry
Acetamides pharmacology
Antitubercular Agents pharmacology
Antitubercular Agents chemical synthesis
Antitubercular Agents chemistry
Microbial Sensitivity Tests
Mycobacterium tuberculosis drug effects
Quinolines pharmacology
Quinolines chemistry
Quinolines chemical synthesis
Subjects
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