Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes

Background: The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its metabolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans. Methods: We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes. Results: The median concentration of isoquine that inhibited 50% of parasite growth (IC₅₀) was 9 nM, compared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86. Conclusions: The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC₅₀<10 nM, warrants its further development as an antimalarial.