Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
J Med Chem. 2013 Mar 28;56(6):2556-67. doi: 10.1021/jm400012e. Epub 2013 Mar 13.
Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.
克氏锥虫病是由细胞内原生动物寄生虫克氏锥虫引起的，而目前的药物在安全性和疗效方面都不尽如人意。在最近一次报道的高通量筛选活动之后，我们围绕一类基于咪唑的化合物探索了初步的结构-活性关系。这种分析揭示了化合物 4c（NEU321）和 4j（NEU704），它们对 T. cruzi 的体外培养具有很强的活性，并且对宿主细胞的选择性超过 160 倍。我们报告了 4c 的体外药物代谢和特性分析，并表明这种化学型抑制 T. cruzi CYP51 酶，这一观察结果通过 X 射线晶体学分析得到了证实。我们比较了 4c 与其他先前报道的抑制剂的结合取向。我们表明，4c 与其他先前报道的抑制剂相比，具有更好的配体效率和更短的合成路线，因此应被视为进一步优化的有前途的先导化合物。
