Reversal of chloroquine and mefloquine resistance in Plasmodium falciparumby the two monoindole alkaloids, icajine and isoretuline

Eight naturally occurring monoindole alkaloids were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combinat ion, to reverse the resistance of a chloroquine-resistant strain of Plasmod ium falciparum. None of these indole alkaloids has significant intrinsic an tiplasmodial activity (IC50 > 10 muM or 5 mug/ml). Nevertheless, three alka loids (icajine, isoretuline and strychnobrasiline) did reverse chloroquine resistance at concentrations between 2.5 and 25.4 g/ml (IF of 12.82 for iso retuline on W2 strain). The Interaction Factor (IF) equals 2, < 2, or > 2 f or additive, antagonistic or synergistic effects of alkaloids on chloroquin e inhibition, respectively. Icajine and isoretuline were also assessed in v itro for their mefloquine potentiating activity on a mefloquine-resistant s train of Plasmodium falciparum. Only icajine proved to be synergistic with mefloquine (IF = 15.38).