Open AccessDesign, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity
Author(s) -
Guilherme Fernandes,
Paula Carolina de Souza,
Elsa MorenoViguri,
Mery SantivañezVeliz,
Rocío Paucar,
Silvia PérezSilanes,
Konstantin Chegaev,
Stefano Guglielmo,
Loretta Lazzarato,
Roberta Fruttero,
Chung Man Chin,
Patrícia Bento da Silva,
Marlus Chorilli,
Mariana Cristina Solcia,
Camila M. Ribeiro,
Caio Sander Paiva Silva,
Leonardo Biancolino Marino,
Priscila Longhin Bosquesi,
David M. Hunt,
Luiz Pedro S. de Carvalho,
Carlos Alberto de Souza Costa,
SangHyun Cho,
Yuehong Wang,
Scott G. Franzblau,
Fernando R. Pavan,
Jean Leandro dos Santos
Publication year - 2017
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b01332
Subject(s) - in vivo , chemistry , mycobacterium tuberculosis , lead compound , tuberculosis , in vitro , bioavailability , pharmacology , chemical synthesis , mode of action , combinatorial chemistry , biochemistry , biology , medicine , microbiology and biotechnology , pathology
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 MIC 90 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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