Structure-activity relationships of 4-N-substituted ferroquine analogues: Time to re-evaluate the mechanism of action of ferroquine

A series of five new alkyl 4-N-substituted analogues of ferroquine (FQ, SR97193) were designed, synthesized, and characterized. The antimalarial activity of the compounds was measured against twelve strains of Plasmodium falciparum. The compounds were more active than chloroquine (CQ) against all the CQ-resistant clones. For a better understanding of their mechanism of action, their physicochemical properties (lipophilicity and basicity) and their action on the inhibition of beta-hematin formation were evaluated. The importance of the intramolecular hydrogen bond in neutral FQ in the antimalarial activity was probed, compared to the methyl analogue 1. Results of additional physicochemical measurements suggested new insights into the mechanism of action of FQ in sharp contrast with CQ. We complement here our understanding on the mechanism of action of FQ with the process of catalysis-mediated hemozoin formation at the interface between vacuolar content and membrane lipids. (C) 2008 Elsevier B. V. All rights reserved.