Activity of and initial mechanistic studies on a novel antileishmanial agent identified through in silico pharmacophore development and database searching.
Activity of and initial mechanistic studies on a novel antileishmanial agent identified through in silico pharmacophore development and database searching.
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通过计算机药效团开发和数据库搜索鉴定出一种新型抗利什曼病药物的活性和初步机制研究。
DOI：
10.1021/jm060156v
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Werbovetz,KarlA
中科院分区：
文献类型：
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作者：
Delfin,DawnA;Bhattacharjee,ApurbaK;Yakovich,AdamJ;Werbovetz,KarlA
采用CATALYST 3D-QSAR方法构建了二硝基苯胺磺酰胺类化合物抗利什曼原虫活性的三维药效团，并将其用于Maybridge数据库的检索。在该搜索中鉴定的两个化合物BTB 06237和BTB 06256对杜氏利什曼原虫无鞭毛体具有高度活性，IC 50值分别为0.5 ± 0.2和2.3 ± 0.8 μM。BTB 06237还降低了L.墨西哥感染的J774巨噬细胞在低微摩尔浓度。与二硝基苯胺磺酰胺不同，活性化合物对利什曼原虫没有显示出抗有丝分裂作用。透射电子显微镜显示，单个寄生虫的寄生虫体与BTB 06237孵育后扩张，荧光显微镜显示，当用寄生虫体特异性染料处理时，该细胞器碎片进入强烈染色的球体。线粒体膜电位也消散在BTB 06237处理的寄生虫。这些结果表明，BTB 06237是一种有趣的抗利什曼原虫先导化合物，可能干扰线粒体功能。
A 3D pharmacophore was generated to describe the antileishmanial activity of dinitroaniline sulfonamides by CATALYST 3D-QSAR methodology, and this pharmacophore was used to search the Maybridge database. Two compounds identified in this search, BTB 06237 and BTB 06256, were highly active with IC50values againstL.donovaniamastigotes of 0.5 ± 0.2 and 2.3 ± 0.8 μM, respectively. BTB 06237 also reduced parasite burdens inL. mexicana-infected J774 macrophages at low micromolar concentrations. Unlike the dinitroaniline sulfonamides, the active compounds did not display antimitotic effects againstLeishmania. Transmission electron microscopy showed that the single parasite mitochondrion becomes dilated following incubation with BTB 06237, and fluorescence microscopy demonstrated that this organelle fragments into intensely staining spheres when treated with a mitochondrion-specific dye. The mitochondrial membrane potential was also dissipated in BTB 06237-treated parasites. These results indicate that BTB 06237 is an intriguing antileishmanial lead compound that likely interferes with mitochondrial function.