Design, Synthesis and Characterization of N-oxide-containing Heterocycles with In vivo Sterilizing Antitubercular Activity

Abstract

Tuberculosis, caused by the 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 non- replicating 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 the reduction of the number of Mtb to undetected levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks the process of translation. Altogether, these results indicated benzofuroxan derivative 8 to be a promising lead compound for the development of a novel chemical class of antitubercular drugs.