Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease that killed ca. 1.4 million people in 2015. It is believed that one-third of the world population is infected with TB and ~9 million new infections are reported every year. The current therapy for drug-sensitive infection consists of isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), and ethambutol (EMB). However, multi drug resistant (MDR) and extended-drug resistant (XDR) M. tuberculosis strains have emerged to the current therapy. Therefore, new antitubercular drugs, with a novel mechanism of action are needed to target drug-resistant as well as dormant/persistent strains. We report the optimization and biological evaluation of novel analogs of a diamide screening hit (MIC = 0.39 µM towards M. tuberculosis H37Rv). The novel analogs, exhibited significant improvements in their in vitro efficacy, physiochemical, ADMET, and pharmacokinetic profiles, enabling their further study as chemical tools and drug discovery entities.

Synthesis, optimization, and biological evaluation of novel analogs of DG85 as antitubercular agents

254th National Meeting (2017)

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