Unveiling the Antimycobacterial Potential of Novel 4-Alkoxyquinolines: Insights into Selectivity, Mechanism of Action, and <i>In Vivo</i> Exposure
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 <i>Mycobacterium tuberculosis</i> strains. The lead molecule, targeting the cytochrome <i>bc</i><sub>1</sub> complex, exhibited favorable kinetic solubility and remarkable chemical stability under acidic conditions. Despite <i>in vitro</i> 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 <i>in vivo</i> exposure following gavage in mice, with an AUC<sub>0-<i>t</i></sub> 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.
Authors
- Fernanda Fries da Silva
- Marcia Alberton Perelló
- Lovaine Silva Duarte (ORCID: https://orcid.org/0000-0001-7054-6277)
- Mauro Neves Muniz
- Guilherme Arraché Gonçalves (ORCID: https://orcid.org/0000-0003-1318-7380)
- Anelise Baptista da Silva (ORCID: https://orcid.org/0000-0001-9758-3289)
- Cristiano Valim Bizarro (ORCID: https://orcid.org/0000-0002-2609-8996)
- Josiane Delgado Paz
- Raoní Scheibler Rambo (ORCID: https://orcid.org/0000-0002-5335-2654)
- Pablo Machado (ORCID: https://orcid.org/0000-0001-5616-9583)
- Alexia de Matos Czeczot (ORCID: https://orcid.org/0000-0001-9678-7597)
- Sı́lvia Dias de Oliveira (ORCID: https://orcid.org/0000-0002-7296-5085)
- Laura Calle González (ORCID: https://orcid.org/0000-0002-1664-1457)
- Luiz Augusto Basso (ORCID: https://orcid.org/0000-0003-0903-2407)
- Carlos Alexandre Sanchez Ferreira (ORCID: https://orcid.org/0000-0002-3727-5097)
- Sidnei Moura (ORCID: https://orcid.org/0000-0003-1903-6735)
- Andresa Berger
Institutions
- Universidade de Caxias do Sul (BR)
- Instituto de Medicina Tropical (PY)
- Deoxi Biotecnologia (Brazil) (BR)
- Sociedade Brasileira de Biologia Celular (BR)
- Pontifícia Universidade Católica do Rio Grande do Sul (BR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01302
- Citations
- 4
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 1.56
Funders
- Instituto Nacional de Ciência e Tecnologia em Tuberculose
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- Fundação de Desenvolvimento de Tecnópolis
- Banco Nacional de Desenvolvimento Econômico e Social