Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
ChemMedChem. 2011 Feb 7;6(2):334-42. doi: 10.1002/cmdc.201000490. Epub 2011 Jan 21.
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.
结核病（TB）的斗争仍远未结束。结核病由结核分枝杆菌引起，是全球最致命的传染病之一。与人类免疫缺陷病毒（HIV）的合并感染以及耐多药结核病（MDR-TB）和广泛耐药结核病（XDR-TB）菌株的出现，进一步增加了这种疾病的负担。在此，我们报告了 2-(4-氯苄基）-3-甲基-1-氧代-1H,5H-吡啶并[1,2-a]苯并咪唑-4-甲腈作为一种有效的抗结核药物的发现，以及对该分子的结构修饰，这些修饰导致了具有更高效力和更低毒性的类似物。这些衍生物中的一些在亚微米浓度下对耐药结核菌株也具有活性，并且对 Vero 细胞没有明显的毒性，这突出了它们作为开发新的抗结核药物的新型支架的价值。
