Pyrido[1,2-a]benzimidazole-Based Agents Active Against Tuberculosis (TB), Multidrug-Resistant (MDR) TB and Extensively Drug-Resistant (XDR) TB

The struggle against tuberculosis (TB) is still far from over. TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. Co-infection with human immunodeficiency virus (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. Herein, we report the discovery of 2-(4-chlorobenzyl)-3-methyl-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole-4-carbonitrile as an effective antitubercular agent and the structural modifications of this molecule that have led to analogues with improved potency and lower toxicity. A number of these derivatives were also active at sub-micromolar concentrations against resistant TB strains and devoid of apparent toxicity to Vero cells, thereby underscoring their value as novel scaffolds for the development of new anti-TB drugs. Waging war on TB: Using high-throughput screening, we have identified a pyrido[1,2-a]benzimidazole as a potent antitubercular agents. Chemical modifications to the hit compound led to an analogue (3h) with improved potency and reduced toxicity. Of considerable interest was the finding that 3h maintained activity against two extensively drug-resistant strains and one multidrug-resistant strain of tuberculosis (TB). These compounds represent promising leads in the quest for improved anti-TB drugs. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.