Evaluation of In Vitro Inhibition of -Hematin Formation: A Step Towards a Comprehensive Understanding of the Mechanism of Action of New Arylamino Alcohols.

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the -hematin inhibition capacity of three pairs of enantiopure AAAs ( and ) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of -hematin-the synthetic counterpart of hemozoin formation-was determined for each compound. Antimalarial activity against W2 and 3D7 strains as well as percentages of inhibition of -hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit -hematin formation and low cytotoxicity, AAAs and are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.