title: Searching for new antimalarial therapeutics amongst known drugs.
abstract: The need to discover and develop new antimalarial therapeutics is overwhelming. The annual mortality attributed to malaria, currently approximately 2.5 million, is increasing due primarily to widespread resistance to currently used drugs. One strategy to identify new treatment alternatives for malaria is to examine libraries of diverse compounds for the possible identification of novel scaffolds. Beginning with libraries of drug or drug-like compounds is an ideal starting point because, in the case of approved drugs, substantial pharmacokinetic and toxicologic data should be available for each compound series. We have employed a high-throughput screen of the MicroSource Spectrum and Killer Collections, a library of known drugs, bioactive compounds, and natural products. Our screening assay identifies compounds that inhibit growth of Plasmodium falciparum cultured in human erythrocytes. We have identified 36 novel inhibitors of P. falciparum, of which 19 are therapeutics, and five of these drugs exhibit effective 50% inhibitory concentrations within similar ranges to therapeutic serum concentrations for their recently indicated uses: propafenone, thioridazine, chlorprothixene, perhexiline, and azlocillin. The findings we report here indicate that this is an effective strategy to identify novel scaffolds and therefore aid in antimalarial drug discovery efforts.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California 94158-2542, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Weisman
authors.forename: Ally P
authors.initials: AP
authors.lastname: Liou
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Fred E
authors.initials: FE
authors.lastname: Cohen
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects
chemical_list: D000962:Antimalarials