title: Antimalarial activity of novel 5-aryl-8-aminoquinoline derivatives.
abstract: In an attempt to separate the antimalarial activity of tafenoquine (3) from its hemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficiency patients, a series of 5-aryl-8-aminoquinoline derivatives was prepared and assessed for antimalarial activities. The new compounds were found metabolically stable in human and mouse microsomal preparations, with t(1/2) > 60 min, and were equal to or more potent than primaquine (2) and 3 against Plasmodium falciparum cell growth. The new agents were more active against the chloroquine (CQ) resistant clone than to the CQ-sensitive clone. Analogues with electron donating groups showed better activity than those with electron withdrawing substituents. Compounds 4bc, 4bd, and 4be showed comparable therapeutic index (TI) to that of 2 and 3, with TI ranging from 5 to 8 based on IC(50) data. The new compounds showed no significant causal prophylactic activity in mice infected with Plasmodium berghei sporozoites, but are substantially less toxic than 2 and 3 in mouse tests.
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiraki
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kozar
authors.forename: Victor
authors.initials: V
authors.lastname: Melendez
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hudson
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Magill
authors.forename: Ai J
authors.initials: AJ
authors.lastname: Lin
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000517:prevention & control; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D002738:Chloroquine