In vitro reversal of chloroquine resistance in Plasmodium falciparum with dihydroethanoanthracene derivatives.

Abstract

Abstract. The effects of combining four dihydroethanoanthracenic (DEA) derivatives and chloroquine were assessed in vitro against Plasmodium falciparum chloroquine resistant parasites W2, Palo Alto, FCR3, and Bres1. Like verapamil or promethazine, the four dihydroethanoanthracenic derivatives tested can be added to the growing list of agents that show capability in enhancing the activity of chloroquine against resistant parasites. The structurally related tricyclic antihistaminic compounds examined in this study exerted different intrinsic antimalarial activity, but the same chloroquine-potentiating activity as verapamil or promethazine. They may act both on the rate of chloroquine accumulation and on its access to ferriprotoporphyrin IX. The reversal mechanism would be assumed to result from competition between DEA derivatives and chloroquine for efflux translocation sites, thus causing an increase in steadystate accumulation of chloroquine and a return to susceptibility. Restoration of therapeutic efficacy of chloroquine against resistant parasites by the administration of an additional drug available at relatively low cost may be a more effective strategy than the introduction of another antimalarial drug at the national level.

Chloroquine Resistance Reversal Agents as Promising Antimalarial Drugs

“…Actually, verapamil at concentrations ranging from 2 to 10 µM is able to increase the level of CQ accumulation in CQ-resistant parasites by two-to six fold [7,9,[143][144][145][146]. Verapamil, when used at concentrations between 0.5 µM to 1 µM, has been found to reverse CQ resistance from 40% till 85% [147][148][149][150]. CQ has little morpho- Fig.…”

“…8) have been shown to reverse resistance to CQ of several strains and isolates [136,150,188,189]. Some of these compounds increase the CQ accumulation in CQ-resistant P. falciparum parasites five to eight times more than promethazine does, whereas others dihydroethanoanthracenic reversal agents have no effect [144].…”

Polymorphism in Plasmodium falciparum Drug Transporter Proteins and Reversal of In Vitro Chloroquine Resistance by a 9,10-Dihydroethanoanthracene Derivative

“…Several compounds, such as verapamil (VER) (15,22), desipramine (3,5), and antihistaminic drugs (13,18), have demonstrated in the past decade a promising capacity to reverse CQ resistance in parasite isolates in vitro, in animal models, and in human patients with malaria. The capacity of 9,10-dihydroethanoanthracenes to reverse the CQ resistance of several strains and isolates was shown previously (2,17,19,20).…”

Clerodane diterpenes from Polyalthia longifolia (Sonn) Thw. var. pendula: Potential antimalarial agents for drug resistant Plasmodium falciparum infection

“…Chloroquine is more available, inexpensive and affordable; hence the development of an agent that can increase its accumulation in drug resistant parasites (Pradines et al, 2002) may enable the reuse of this drug in regions with chloroquine-resistant malaria and help reduce their malaria burden. In our study, the isobolic curves constructed for the various combination solutions depicted the interactions of chloroquine with the isolates (Fig.…”