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

2011; Wiley; Volume: 6; Issue: 2 Linguagem: Inglês

10.1002/cmdc.201000490

1860-7187

Marco Pieroni, Suresh K. Tipparaju, Shichun Lun, Yang Song, A. Willem Sturm, William R. Bishai, Alan P. Kozikowski,

Synthesis and biological activity

Abstract 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‐1 H ,5 H ‐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.