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

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

Design, Synthesis, and Characterization of N‑Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by Mycobacterium tuberculosis (<i>Mtb</i>), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by <i>in vitro</i> and <i>in vivo</i> evaluation of their antitubercular potential against <i>Mtb</i>. Compound <b>8</b> was found to be the most promising compound, with MIC₉₀ values of 1.10 and 6.62 μM against active and nonreplicating <i>Mtb</i>, respectively. Additionally, we carried out <i>in vivo</i> experiments to confirm the safety and efficacy of compound <b>8</b>; the compound was found to be orally bioavailable and highly effective, leading to a reduction of <i>Mtb</i> to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound <b>8</b> blocks translation. Altogether, these results indicate that benzofuroxan derivative <b>8</b> is a promising lead compound for the development of a novel chemical class of antitubercular drugs