Exploring Scaffold Hopping for Novel 2-(Quinolin-4-yloxy)acetamides with Enhanced Antimycobacterial Activity

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

doi:10.1021/acsmedchemlett.3c00570

Exploring Scaffold Hopping for Novel 2-(Quinolin-4-yloxy)acetamides with Enhanced Antimycobacterial Activity

ACS Med Chem Lett. 2024 Mar 11;15(4):493-500. doi: 10.1021/acsmedchemlett.3c00570. eCollection 2024 Apr 11.

Authors

Ana Flávia Borsoi^{1

2}, Alessandro Silva Ramos¹, Nathalia Sperotto¹, Bruno Lopes Abbadi¹, Fernanda Souza Macchi Hopf^{1

3}, Adilio da Silva Dadda¹, Raoní Scheibler Rambo¹, Mauro Neves Muniz¹, Josiane Delgado Paz¹, Estevão Silveira Grams^{1

3}, Fernanda Fries da Silva^{1

3}, Kenia Pissinate¹, Luiza Galina¹, Laura Calle González^{1

3}, Lovaine Silva Duarte¹, Marcia Alberton Perelló¹, Alexia de Matos Czeczot^{1

3}, Cristiano Valim Bizarro^{1

3}, Luiz Augusto Basso^{1

2

3}, Pablo Machado^{1

2

3}

Affiliations

¹ Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.
² Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.
³ Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, 90616-900 Porto Alegre, Rio Grande do Sul, Brazil.

PMID: 38628799
PMCID: PMC11017393 (available on 2025-04-11)
DOI: 10.1021/acsmedchemlett.3c00570

Abstract

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 bc₁ complex is the likely target. Additionally, these structures showed high selectivity regarding mammalian cells (selectivity index > 500) and stability across different aqueous media. Furthermore, some of the synthesized quinolines demonstrated aqueous solubility values that exceeded those of telacebec, while maintaining low rates of metabolism. Finally, a selected compound prevented Mtb growth by more than 1.7 log₁₀ colony forming units in a macrophage model of tuberculosis (TB) infection. These findings validate the proposed design and introduce new 2-(quinolin-4-yloxy)acetamides with potential for development in TB drug discovery campaigns.