title: Relationship between antimalarial drug activity, accumulation, and inhibition of heme polymerization in Plasmodium falciparum in vitro.
abstract: We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.
authors.affiliation: Department of Human Anatomy and Cell Biology, University of Liverpool, United Kingdom.
authors.forename: S R
authors.initials: SR
authors.lastname: Hawley
authors.forename: P G
authors.initials: PG
authors.lastname: Bray
authors.forename: M
authors.initials: M
authors.lastname: Mungthin
authors.forename: J D
authors.initials: JD
authors.lastname: Atkinson
authors.forename: P M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D015195:Drug Design; D004351:Drug Resistance; D006418:Heme / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D011108:Polymers; D012680:Sensitivity and Specificity
chemical_list: D000962:Antimalarials; D011108:Polymers; D006418:Heme; D002738:Chloroquine