|
|||||
|
|
Structure-activity relationships of 4-N-substituted ferroquine analogues: Time to re-evaluate the mechanism of action of ferroquine |
|
| Authors: | Christophe Biot Natascha Chavain Bruno Pradines Jacques Brocard Daniel Dive |
| Affiliation: | a Université des Sciences et Technologies de Lille, Unité de Catalyse et Chimie du Solide - UMR CNRS 8181, Ecole Nationale Supérieure de Chimie de Lille, Bâtiment C7, B.P. 90108, 59652 Villeneuve d’ Ascq cedex, France b Institut de Médecine Tropicale du Service de Sante des Armées, Unité de Recherche en Biologie et Epidémiologie Parasitaires - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes UMR 6236, Bd Charles Livon, Parc le Pharo, B.P. 46, 13998 Marseille Armées, France c Université des Sciences et Technologies de Lille, Laboratoire de Glycobiologie Structurale et Fonctionnelle, UMR CNRS 8576, Bâtiment C4/C9, 59655 Villeneuve d’Ascq cedex, France d EA 4138 Pharmacochimie, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France e Inserm U547, Institut Pasteur, 1 rue du Pr Calmette, B.P. 245, 59019 Lille cedex, France |
| Abstract: | 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 Plasmodiumfalciparum. 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 β-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. |
| Keywords: | Bioorganometallic chemistry Antimalarial Ferroquine Lipophilicity Mechanism of action |
| 本文献已被 ScienceDirect 等数据库收录！ | |