Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

Jelena Srbljanović, Tijana Štajner, Jelena Konstantinović, Nataša Terzić-Jovanović, Aleksandra Uzelac, Branko Bobić, Bogdan A. Šolaja, Olgica Djurković-Djaković

Malaria remains a major disease of the developing world and globally the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials including chloroquine (CQ), new drugs are urgently needed. We here report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by an LDH assay in cultures of a CQ-sensitive (3D7) and a CQ-resistant (Dd2) strain of Plasmodium falciparum. Of a series of 26 screened compounds, those 12 that exerted a growth inhibition rate of at least 50% were further examined in vitro, to determine the IC50 values, and in vivo. This way, even the four compounds that exhibited high IC50 values, were evaluated in vivo, in a modified Thompson test, in C57BL/6 mice infected with the P. berghei ANKA strain. However, another three compounds were eventually excluded due to toxicity in mice. All nine compounds examined in vivo prolonged survival of treated vs. untreated mice, four of which afforded at least a 60% survival. Most notably, two of these, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). One of these, interestingly, had no in vitro effect (against the CQR strain). Better in vivo than in vitro results suggest a role for the compound metabolites. The presented results point to adamantane as a carrier which enhances the antimalarial potential of aminoquinolines.