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

Abstract

Malaria remains a major disease in the developing world and globally is 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. Here we 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 a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falciparum. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of ≥50% were further examined in vitro to determine the 50% inhibitory concentration (IC) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium berghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded ≥60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ-resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines.

New 4-aminoquinolines as moderate inhibitors of P. falciparum malaria

“…However, these results should be taken with caution since 3 experimental animals died on day 7 (D7), indicating no activity. Of the two mice that survived to D31, one had a positive blood smear and was therefore not cured, but the other one (1/6 tested) was cured based on a negative blood smear as well as absence of detection of P. berghei DNA by PCR (performed as previously described 31 of blood, liver, and spleen. At concentrations of 160 and 80 (mg/kg)/day only suppression activity was observed.…”