Phenyl beta-methoxyacrylates: A new antimalarial pharmacophore

Phenyl beta-methoxyacrylates, linked to an aromatic ring via an olefinic br idge, 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 relationsh ips affecting antimalarial activity. It was found that the beta-methoxyacry late was required ortho to the linker and the optimal bridge was (E,E)-buta diene, Compounds in which the second aromatic ring was ortho-substituted or ortho,para-disubstituted gave optimal potency. Several compounds were iden tified with potency that is superior to that of chloroquine both in culture and in a murine malaria model.