title: Reversal of chloroquine and mefloquine resistance in Plasmodium falciparum by the two monoindole alkaloids, icajine and isoretuline.
abstract: Eight naturally occurring monoindole alkaloids were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance of a chloroquine-resistant strain of Plasmodium falciparum. None of these indole alkaloids has significant intrinsic antiplasmodial activity (IC(50) > 10 microM or 5 microg/ml). Nevertheless, three alkaloids (icajine, isoretuline and strychnobrasiline) did reverse chloroquine resistance at concentrations between 2.5 and 25 microg/ml (IF of 12.82 for isoretuline on W2 strain). The Interaction Factor (IF) equals 2, < 2, or > 2 for additive, antagonistic or synergistic effects of alkaloids on chloroquine inhibition, respectively. Icajine and isoretuline were also assessed in vitro for their mefloquine potentiating activity on a mefloquine-resistant strain of Plasmodium falciparum. Only icajine proved to be synergistic with mefloquine (IF = 15.38).
authors.affiliation: Laboratoire de Pharmacognosie, Institut de Pharmacie, Université de Liège, Belgium. M.Frederich@ulg.ac.be
authors.forename: M
authors.initials: M
authors.lastname: Frédérich
authors.forename: M P
authors.initials: MP
authors.lastname: Hayette
authors.forename: M
authors.initials: M
authors.lastname: Tits
authors.forename: P
authors.initials: P
authors.lastname: De Mol
authors.forename: L
authors.initials: L
authors.lastname: Angenot
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology*; D003106:Colon / Q000166:cytology; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D015767:Mefloquine / Q000494:pharmacology*; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013331:Strychnine / Q000031:analogs & derivatives / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D007211:Indoles; C073235:isoretuline; C438914:icajine; D002738:Chloroquine; D013331:Strychnine; D015767:Mefloquine