Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 20, Pages 8647-8660Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01332
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Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/14957-5, 2014/02240-1, 2014/24811-0, 2014/11586-9, 2014/03920-6, 2015/19531-1, 2016/09502-7, 2016/02860-5]
- Programa de Estagio no Exterior (PROPG-UNESP)
- Conselho National de Desenvolvimento Cientifico e Tecnologico (CNPQ) [162676/2013-1]
- Programa de Apoio ao Desenvolvimento Cientifico da Faculdade de Ciencias Farmaceuticas da UNESP (PADC-FCF UNESP)
- USA National Institute of Allergy and Infections Diseases [HHSN272201100009]
- Francis Crick Institute
- Cancer Research UK [FC001060]
- UK Medical Research Council [FC001060]
- Wellcome Trust [FC001060]
- The Francis Crick Institute [10060] Funding Source: researchfish
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [14/03920-6] Funding Source: FAPESP
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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 mu M 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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