Ana Flávia Borsoi, Alessandro Silva Ramos, Nathalia Sperotto, Bruno Lopes Abbadi, Fernanda Souza Macchi Hopf, Adilio da Silva Dadda, Raoní Scheibler Rambo, Mauro Neves Muniz, Josiane Delgado Paz, Estevão Silveira Grams, Fernanda Fries da Silva, Kenia Pissinate, Luiza Galina, Laura Calle González, Lovaine Silva Duarte, Marcia Alberton Perelló, Alexia de Matos Czeczot, Cristiano Valim Bizarro, Luiz Augusto Basso, Pablo Machado
Utilizing a scaffold-hopping strategy from the drug candidate telacebec, a novel series of 2-(quinolin-4-yloxy)acetamides was synthesized and evaluated as inhibitors of Mycobacterium tuberculosis (Mtb) growth. These compounds demonstrated potent activity against drug-sensitive and multidrug-resistant strains (MIC ≤ 0.02 μM). Leading compounds were evaluated against a known qcrB resistant strain (T313A), and their loss in activity suggested that the cytochrome bc 1 complex is the likely target. Additionally, these structures showed high selectivity regarding mammalian cells (selectivity index > 500) and stability across different aqueous media...
April 11, 2024: ACS Medicinal Chemistry Letters