Exploration of imidazothiazole and imidazopyrimidine carboxamides for enhanced antitubercular activity

Tuberculosis (TB) is an insidious disease that has been around for many centuries. The advent of multidrug-resistant strains of TB has caused a significant setback in eradicating this disease; most importantly, there are limited safe therapeutics available to combat multidrug- and extensively drug-resistant (MDR and XDR, respectively) strains of TB, hence the race to find highly effective antitubercular drug candidates with little to no side effects. Herein, we report on the design, synthesis, and biological evaluation of 33 novel heterobicyclic (imidazothiazole- and imidazopyrimidine-containing) carboxamide derivatives for their antitubercular properties. These compounds were designed based on reported anti-TB properties of indole-2-carboxamides, imidazo[1,2-a]pyridine-3-carboxamides, and imidazo[2,1-b]pyrimidine-5-carboxamides derivatives. This effort led to the discovery of compounds 21 (imidazothiazole-based) and 37 (imidazopyrimidine-based), which showed excellent anti-TB activity against susceptible, MDR, and XDR-TB strains (MIC: 0.2-6.36 μM). Compound 21 also displayed excellent drug-like properties based on its pharmacokinetic profiles and is void of cytotoxicity to Vero cells at the highest tested concentration. Importantly, compounds 21 and 37 were found to be inactive against selected non-TB forming mycobacteria (MIC: >40 μM) and bacteria (both gram-negative and gram-positive Microorganisms), indicating their selectivity for Mycobacterium tuberculosis.

Drug-resistant Mtb; Imidazo[2,1-b]pyrimidine-5-carboxamides; Imidazo[2,1-b]thiazole-5-carboxamides; Imidazopyrimidine; Imidothiazole; Mycobacterium tuberculosis; Structure–activity relationships.