Journal of Medicinal Chemistry 2000-02-24

Phenyl beta-methoxyacrylates: a new antimalarial pharmacophore.

J Alzeer, J Chollet, I Heinze-Krauss, C Hubschwerlen, H Matile, R G Ridley

Index: J. Med. Chem. 43(4) , 560-8, (2000)

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Abstract

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.