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.

中文翻译：

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在针对细菌细胞分裂蛋白 FtsZ 的新一代抗结核药物发现中战略性掺入氟。


本文介绍了我们针对 FtsZ 靶向耐药结核病的新一代含氟抗菌药物的发现和开发研究。 FtsZ 是细菌细胞分裂的必需蛋白，也是抗菌药物研发中极具前景的治疗靶点。通过新型苯并咪唑库的设计、合成和半 HTP 筛选，随后进行 SAR 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和血浆稳定性。因此，我们对将氟战略性地掺入先导化合物以改善药理特性进行了广泛的研究。这项研究导致了高效含氟苯并咪唑作为潜在候选药物的开发。我们还对这些新型 FtsZ 抑制剂进行了计算对接分析，以确定其假定的结合位点。基于结构数据和对接分析，提出了此类新型 FtsZ 抑制剂的合理作用模式。