Delfín Dawn A, Bhattacharjee Apurba K, Yakovich Adam J, Werbovetz Karl A
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Parks Hall Room 331, 500 West 12th Avenue, Columbus, 43210, USA.
J Med Chem. 2006 Jul 13;49(14):4196-207. doi: 10.1021/jm060156v.
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 IC(50) values against L. donovani amastigotes of 0.5 +/- 0.2 and 2.3 +/- 0.8 microM, respectively. BTB 06237 also reduced parasite burdens in L. mexicana-infected J774 macrophages at low micromolar concentrations. Unlike the dinitroaniline sulfonamides, the active compounds did not display antimitotic effects against Leishmania. 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.
采用CATALYST 3D-QSAR方法生成了一个3D药效团，以描述二硝基苯胺磺酰胺的抗利什曼原虫活性，并使用该药效团搜索Maybridge数据库。在此次搜索中鉴定出的两种化合物，BTB 06237和BTB 06256，活性很高，对杜氏利什曼原虫无鞭毛体的IC(50)值分别为0.5±0.2和2.3±0.8微摩尔。BTB 06237在低微摩尔浓度下也能降低墨西哥利什曼原虫感染的J774巨噬细胞中的寄生虫负荷。与二硝基苯胺磺酰胺不同，活性化合物对利什曼原虫没有抗有丝分裂作用。透射电子显微镜显示，与BTB 06237孵育后，单个寄生虫线粒体膨胀，荧光显微镜显示，用线粒体特异性染料处理后，该细胞器破碎成强烈染色的球体。在BTB 06237处理的寄生虫中，线粒体膜电位也消失了。这些结果表明，BTB 06237是一种引人关注的抗利什曼原虫先导化合物，可能干扰线粒体功能。
