Aminoquinolines afford resistance to cerebral malaria in susceptible mice

Abstract

Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines.

Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQ^R) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain.

Results: Nine of the ten compounds had a lower 50% inhibitory concentration (IC₅₀) than CQ against the CQ^R strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31.

Conclusions: The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQ^RP. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.

Keywords: Aminoquinolines; C57BL/6 mice; Hyperparasitaemia; Malaria; Plasmodium berghei.