Alzeer J, Chollet J, Heinze-Krauss I, Hubschwerlen C, Matile H, Ridley R G
Pharma Research, Preclinical Infectious Diseases, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
J Med Chem. 2000 Feb 24;43(4):560-8. doi: 10.1021/jm990002y.
Phenyl beta-methoxyacrylates, linked to an aromatic ring via an olefinic bridge, have been identified as novel, potentially inexpensive, antimalarial agents. The compounds are believed to exert their activity by inhibition of mitochondrial electron transport at the cytochrome bc(1) complex. A series of compounds have been synthesized to define structure-activity relationships affecting antimalarial activity. It was found that the beta-methoxyacrylate was required ortho to the linker and the optimal bridge was (E,E)-butadiene. Compounds in which the second aromatic ring was ortho-substituted or ortho,para-disubstituted gave optimal potency. Several compounds were identified with potency that is superior to that of chloroquine both in culture and in a murine malaria model.
通过烯烃桥连与芳环相连的苯基β-甲氧基丙烯酸酯已被鉴定为新型、可能价格低廉的抗疟药物。据信这些化合物通过抑制细胞色素bc(1)复合物处的线粒体电子传递发挥其活性。已合成了一系列化合物以确定影响抗疟活性的构效关系。发现β-甲氧基丙烯酸酯需位于连接基的邻位，最佳桥连为（E,E）-丁二烯。第二个芳环为邻位取代或邻、对位双取代的化合物具有最佳效力。在培养物和小鼠疟疾模型中均鉴定出几种效力优于氯喹的化合物。
