title: A novel pyrrolidonoalkaneamine (WR268954) that modulates chloroquine resistance of Plasmodium falciparum in vitro.
abstract: With the recent observations of efflux of chloroquine from Plasmodium falciparum and modulation of chloroquine resistance by calcium channel blockers, such as verapamil, a great deal of attention has been focused on the development of new modulators that can potentiate the efficacy of chloroquine. We report a new compound, WR268954, that has weak intrinsic antimalarial activity compared to chloroquine. In vitro, it increased the susceptibilities of chloroquine-resistant P. falciparum strains to chloroquine and quinine, but did not affect the chloroquine-susceptible strains. In the presence of 2,000 nM of WR268954, the 50% inhibitory concentration of chloroquine for drug-resistant P. falciparum decreased 90-fold in comparison with the control (chloroquine only). The same concentration of WR268954 increased the potentiation of chloroquine in resistant strains to a level approximately equivalent to that observed for the sensitive strain. This compound also potentiates the efficacy of quinine in drug-resistant parasites. However, WR268954 did not enhance the efficacy of mefloquine in the mefloquine-resistant parasites. In this report, the data show the synergistic effect of WR268954 on the antimalarial activity of chloroquine in drug-resistant strains of P. falciparum, but only an additive effect on drug-sensitive strains of parasites. Compound WR268954 belongs to a pyrrolidino alkane amine class whose in vitro chloroquine resistance modulator activity supports the basis for the synthesis of this class of compounds.
authors.affiliation: Department of Parasitology, Walter Reed Army Institute of Research, Washington, District of Columbia.
authors.forename: D
authors.initials: D
authors.lastname: De
authors.forename: A P
authors.initials: AP
authors.lastname: Bhaduri
authors.forename: W K
authors.initials: WK
authors.lastname: Milhous
mesh_terms: D000818:Animals; D000840:Anisoles / Q000737:chemistry / Q000494:pharmacology*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology*; D004351:Drug Resistance; D004357:Drug Synergism; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology*; D011803:Quinine / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000840:Anisoles; D000962:Antimalarials; D011759:Pyrrolidines; C082650:WR 268954; D002738:Chloroquine; D011803:Quinine; D014700:Verapamil