title: 2-Oxotetrahydroquinoline-based antimalarials with high potency and metabolic stability.
abstract: We report a series of novel inhibitors of protein farnesyltransferase based on the 2-oxotetrahydroquinoline scaffold. We developed an efficient synthesis of these compounds. These compounds show selective inhibtion of the malaria versus human farnesyltransferase and inhibit the growth of the malaria parasite in the low nanomolar range. Some of the compounds are at least an order of magnitude more stable to metabolic degradation than the corresponding tetrahydroquinolines.
authors.affiliation: Departments of Chemistry, Medicine, and Biochemistry, University of Washington, Seattle, Washington 98195. gelb@chem.washington.edu.
authors.forename: Vivek J
authors.initials: VJ
authors.lastname: Bulbule
authors.forename: Kasey
authors.initials: K
authors.lastname: Rivas
authors.forename: Christophe L M J
authors.initials: CL
authors.lastname: Verlinde
authors.forename: Wesley C
authors.initials: WC
authors.lastname: Van Voorhis
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D011804:Quinolines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase