Antitrypanosomal Lead Discovery: Identification of a Ligand-Efficient Inhibitor of Trypanosoma cruzi CYP51 and Parasite Growth
Antitrypanosomal Lead Discovery: Identification of a Ligand-Efficient Inhibitor of Trypanosoma cruzi CYP51 and Parasite Growth
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DOI：
10.1021/jm400012e
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Pollastri, Michael P.
中科院分区：
文献类型：
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作者：
Andriani, Grasiella;Amata, Emanuele;Pollastri, Michael P.
查加斯病是由细胞内原生动物寄生虫克氏锥虫引起的，目前的药物缺乏所需的安全性和有效性。在最近报道的高通量筛选活动之后，我们已经探索了一类咪唑类化合物的初始结构-活性关系。该分析揭示了化合物4c（NEU 321）和4j（NEU 704），它们对T. Cruzi和对宿主细胞的选择性大于160倍。我们报告了4c的体外药物代谢和性质分析，并表明这种化学型抑制T。cruzi CYP 51酶，这一观察结果得到了X射线晶体学分析的证实。我们比较的结合方向的4C的其他，以前报道的抑制剂。我们表明，4c显示出显着更好的配体效率和较短的合成路线比以前公开的CYP 51抑制剂，因此应该被认为是一个有前途的先导化合物进行进一步优化。
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.