Discovery of antitubercular 2,4-diphenyl-1H-imidazoles from chemical library repositioning and rational design

• Several diphenylimidazoles, designed as sodium channel blockers, have been repurposed as antituberculars.
• Based on the preliminary analysis of the antimycobacterial activity, a small series of analogues with improved activity has been synthesized.
• The wide range of activities allowed us to construct a plausible SAR.
• Some of the novel compounds are active also against the latent phenotype of infection.
• 2,4-Diphenyl-1H-imidazoles represent a novel antiTB chemotype.

TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. The co-infection with HIV and the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains have further increased the burden for this disease. In the attempt to respond to the constant need of novel therapeutic options, we herein report the discovery of 2,4-diphenyl-1H-imidazoles as effective antitubercular agents, with MIC in the low micromolar range against actively replicating and persistent M. tuberculosis strains. The good activity, along with the lack of toxicity and the feasible synthesis, underscore their value as novel scaffolds for the development of new anti-TB drugs.

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