title: Parallel synthesis of 9-aminoacridines and their evaluation against chloroquine-resistant Plasmodium falciparum.
abstract: A parallel synthetic strategy to the 9-aminoacridine scaffold of the classical anti-malarial drug quinacrine (2) is presented. The method features a new route to 9-chloroacridines that utilizes triflates of salicylic acid derivatives, which are commercially available in a variety of substitution patterns. The route allows ready variation of the two diversity elements present in this class of molecules: the tricyclic aromatic heterocyclic core, and the disubstituted diamine sidechain. In this study, a library of 175 compounds was designed, although only 93 of the final products had purities acceptable for screening. Impurity was generally due to incomplete removal of 9-acridones (18), a degradation product of the 9-chloroacridine synthetic intermediates. The library was screened against two strains of Plasmodium falciparum, including a model of the drug-resistant parasite, and six novel compounds were found to have IC(50) values in the low nanomolar range.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94143-2280, USA.
authors.forename: Marc O
authors.initials: MO
authors.lastname: Anderson
authors.forename: John
authors.initials: J
authors.lastname: Sherrill
authors.forename: Peter B
authors.initials: PB
authors.lastname: Madrid
authors.forename: Ally P
authors.initials: AP
authors.lastname: Liou
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Weisman
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000585:Aminacrine / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
chemical_list: D000962:Antimalarials; D000585:Aminacrine; D002738:Chloroquine