Li R, Kenyon G L, Cohen F E, Chen X, Gong B, Dominguez J N, Davidson E, Kurzban G, Miller R E, Nuzum E O
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446, USA.
J Med Chem. 1995 Dec 22;38(26):5031-7. doi: 10.1021/jm00026a010.
A series of chalcones and their derivatives have been synthesized and identified as novel potential antimalarials using both molecular modeling and in vitro testing against the intact parasite. A large number of chalcones and their derivatives were prepared using one-step Claisen-Schmidt condensations of aldehydes with methyl ketones. These condensates were screened in vitro against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and shown to be active at concentrations in the nanomolar range. The most active chalcone derivative, 1-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-1-one (7), had an IC50 value of 200 nM against both a chloroquine-resistant strain (W2) and a chloroquine-sensitive strain (D6). The resistance indexes for all compounds were substantially lower than for chloroquine, suggesting that this series will be active against chloroquine-resistant malaria. Structure-activity relationships (SAR) of the chalcones in the context of a homology-based model structure of the malaria trophozoite cysteine protease, the most likely target enzyme, are presented.
通过分子建模和针对完整寄生虫的体外测试，合成了一系列查尔酮及其衍生物，并将其鉴定为新型潜在抗疟药物。使用醛与甲基酮的一步克莱森-施密特缩合反应制备了大量查尔酮及其衍生物。这些缩合物在体外针对恶性疟原虫的氯喹敏感株和氯喹耐药株进行了筛选，结果表明它们在纳摩尔浓度范围内具有活性。活性最高的查尔酮衍生物1-(2,5-二氯苯基)-3-(4-喹啉基)-2-丙烯-1-酮(7)对氯喹耐药株(W2)和氯喹敏感株(D6)的IC50值均为200 nM。所有化合物的耐药指数均显著低于氯喹，这表明该系列化合物对氯喹耐药疟疾具有活性。本文还介绍了基于同源性模型结构的疟原虫滋养体半胱氨酸蛋白酶（最可能的靶酶）背景下查尔酮的构效关系(SAR)。
