Journal of Medicinal Chemistry p. 8647 - 8660 (2017)
Update date:2022-08-16
Topics:
Dos Santos Fernandes, Guilherme Felipe
De Souza, Paula Carolina
Moreno-Viguri, Elsa
Santiva?ez-Veliz, Mery
Paucar, Rocio
Pérez-Silanes, Silvia
Chegaev, Konstantin
Guglielmo, Stefano
Lazzarato, Loretta
Fruttero, Roberta
Man Chin, Chung
Da Silva, Patricia Bento
Chorilli, Marlus
Solcia, Mariana Cristina
Ribeiro, Camila Maríngolo
Silva, Caio Sander Paiva
Marino, Leonardo Biancolino
Bosquesi, Priscila Longhin
Hunt, Debbie M.
De Carvalho, Luiz Pedro S.
De Souza Costa, Carlos Alberto
Cho, Sang Hyun
Wang, Yuehong
Franzblau, Scott Gary
Pavan, Fernando Rogério
Dos Santos, Jean Leandro
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.
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