title: Phenyl beta-methoxyacrylates: a new antimalarial pharmacophore.
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.
authors.affiliation: Pharma Research, Preclinical Infectious Diseases, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Alzeer
authors.forename: J
authors.initials: J
authors.lastname: Chollet
authors.forename: I
authors.initials: I
authors.lastname: Heinze-Krauss
authors.forename: C
authors.initials: C
authors.lastname: Hubschwerlen
authors.forename: H
authors.initials: H
authors.lastname: Matile
authors.forename: R G
authors.initials: RG
authors.lastname: Ridley
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D008297:Male; D051379:Mice; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; D000962:Antimalarials; D001555:Benzene Derivatives