Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682, USA.
Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
Tuberculosis (Edinb). 2014 May;94(3):271-6. doi: 10.1016/j.tube.2014.03.007. Epub 2014 Apr 1.
Structure based drug design was used to develop a compound library of novel 2,5,6- and 2,5,7-trisubstituted benzimidazoles. Three structural analogs, SB-P1G10, SB-P8B2 and SB-P3G2 were selected from this library for advanced study. In vitro studies revealed that SB-P8B2 and SB-P3G2 had sigmoidal kill-curves while in contrast SB-P1G10 showed a narrow zonal susceptibility. The in vitro studies also demonstrated that exposure to SB-P8B2 or SB-P3G2 was bactericidal, while SB-P1G10 treatment never resulted in complete killing. The dose curves for the three compounds against clinical isolates were comparable to their respective dose curves in the laboratory strain of Mycobacterium tuberculosis. SB-P8B2 and SB-P3G2 exhibited antibacterial activity against non-replicating bacilli under low oxygen conditions. SB-P3G2 and SB-P1G10 were assessed in acute short-term animal models of tuberculosis, which showed that SB-P3G2 demonstrated activity against M. tuberculosis. Together, these studies reveal an in vitro-in vivo relationship of the 2,5,6-trisubstituted benzimidazoles that serves as a criterion for advancing this class of cell division inhibitors into more resource intensive in vivo efficacy models such as the long-term murine model of tuberculosis and Pre-IND PK/PD studies. Specifically, these studies are the first demonstration of efficacy and an in vitro-in vivo activity relationship for 2,5,6-trisubstituted benzimidazoles. The in vivo activity presented in this manuscript substantiates this class of cell division inhibitors as having potency and efficacy against M. tuberculosis.
基于结构的药物设计被用于开发新型 2,5,6-和 2,5,7-三取代苯并咪唑化合物库。从该文库中选择了三个结构类似物，SB-P1G10、SB-P8B2 和 SB-P3G2 进行深入研究。体外研究表明，SB-P8B2 和 SB-P3G2 具有 S 形杀伤曲线，而 SB-P1G10 则表现出狭窄的区域敏感性。体外研究还表明，暴露于 SB-P8B2 或 SB-P3G2 是杀菌的，而 SB-P1G10 处理从未导致完全杀死。三种化合物对临床分离株的剂量曲线与其在结核分枝杆菌实验室株中的相应剂量曲线相当。SB-P8B2 和 SB-P3G2 在低氧条件下对非复制杆菌表现出抗菌活性。SB-P3G2 和 SB-P1G10 被评估用于急性短期结核病动物模型，结果表明 SB-P3G2 对结核分枝杆菌具有活性。总之，这些研究揭示了 2,5,6-三取代苯并咪唑的体外-体内关系，这为将此类细胞分裂抑制剂推进更具资源密集性的体内疗效模型（如长期结核鼠模型和 Pre-IND PK/PD 研究）提供了标准。具体来说，这些研究首次证明了 2,5,6-三取代苯并咪唑的疗效和体外-体内活性关系。本文中提出的体内活性证实了此类细胞分裂抑制剂对结核分枝杆菌具有效力和疗效。
