Francis Crick Inst, Mycobacterial Metab & Antibiot Res Lab, 1 Midland Rd, London NW1 1AT - England
 Sao Paulo State Univ UNESP, Sch Odontol, BR-14801903 Araraquara - Brazil
Total Affiliations: 7
Journal of Medicinal Chemistry;
OCT 26 2017.
Web of Science Citations:
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. (AU)