Ojima Iwao, Awasthi Divya, Wei Longfei, Haranahalli Krupanandan
Department of Chemistry, Stony Brook University-State University of New York, Stony Brook, NY, 11794-3400, USA.
Institute of Chemical Biology & Drug Discovery, Stony Brook University-State University of New York, Stony Brook, NY, 11794-3400, USA.
J Fluor Chem. 2017 Apr;196:44-56. doi: 10.1016/j.jfluchem.2016.07.020. Epub 2016 Jul 29.
This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed.
本文介绍了我们针对耐药结核病发现和开发新一代含氟抗菌剂的研究情况，该研究以FtsZ为靶点。FtsZ是细菌细胞分裂所必需的蛋白质，也是抗菌药物发现中极有前景的治疗靶点。通过对新型苯并咪唑文库进行设计、合成和半高通量筛选，随后开展构效关系研究，我们鉴定出了高效的先导化合物。然而，这些先导化合物被发现缺乏足够的代谢稳定性和血浆稳定性。因此，我们对在先导化合物中战略性引入氟以改善药理性质进行了广泛研究。这项研究促成了作为潜在候选药物的高效含氟苯并咪唑的开发。我们还对这些新型FtsZ抑制剂进行了计算对接分析，以确定它们可能的结合位点。基于结构数据和对接分析，提出了这类新型FtsZ抑制剂合理的作用模式。
