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

Damiani, Céline; Soler, Floriane; Le Govic, Yohann; Totet, Anne; Bentzinger, Guillaume; Bouchut, Anne; Mustière, Romain; Agnamey, Patrice; Dassonville-Klimpt, Alexandra; Sonnet, Pascal

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum 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 β-hematin inhibition capacity of three pairs of enantiopure AAAs 1–3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of β-hematin—the synthetic counterpart of hemozoin formation—was determined for each compound. Antimalarial activity against W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-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 β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a 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.

CYTOTOXINS; DRUG development; PLASMODIUM falciparum; ANTIMALARIALS; MEFLOQUINE; CELL lines

Microorganisms, 2024, Vol 12, Issue 12, p2524

2076-2607

Academic Journal

10.3390/microorganisms12122524