Yao Zhong-Ke, Krai Priscilla M, Merino Emilio F, Simpson Morgan E, Slebodnick Carla, Cassera Maria Belen, Carlier Paul R
Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
Department of Biochemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, United States.
Bioorg Med Chem Lett. 2015 Apr 1;25(7):1515-9. doi: 10.1016/j.bmcl.2015.02.020. Epub 2015 Feb 21.
Compounds that target isoprenoid biosynthesis in Plasmodium falciparum could be a welcome addition to malaria chemotherapy, since the methylerythritol phosphate (MEP) pathway used by the parasite is not present in humans. We previously reported that MMV008138 targets the apicoplast of P. falciparum and that its target in the MEP pathway differs from that of Fosmidomycin. In this Letter, we determine that the active stereoisomer of MMV008138 is 4a, which is (1R,3S)-configured. 2',4'-Disubstitution of the D ring was also found to be crucial for inhibition of the parasite growth. Limited variation of the C3-carboxylic acid substituent was carried out, and methylamide derivative 8a was found to be more potent than 4a; other amides, acylhydrazines, and esters were less potent. Finally, lead compounds 4a, 4e, 4f, 4h, 8a, and 8e did not inhibit growth of Escherichia coli, suggesting that protozoan-selective inhibition of the MEP pathway of P. falciparum can be achieved.
靶向恶性疟原虫类异戊二烯生物合成的化合物可能是疟疾化疗中受欢迎的补充药物，因为该寄生虫所使用的甲基赤藓糖醇磷酸（MEP）途径在人类中不存在。我们之前报道过，MMV008138靶向恶性疟原虫的质体，并且其在MEP途径中的靶点与磷霉素的靶点不同。在这篇信函中，我们确定MMV008138的活性立体异构体是4a，其构型为（1R,3S）。还发现D环的2',4'-二取代对于抑制寄生虫生长至关重要。对C3-羧酸取代基进行了有限的修饰，发现甲基酰胺衍生物8a比4a更具活性；其他酰胺、酰肼和酯的活性较低。最后，先导化合物4a、4e、4f、4h、8a和8e不抑制大肠杆菌的生长，这表明可以实现对恶性疟原虫MEP途径的原生动物选择性抑制。
