title: Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.
abstract: The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.
authors.affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.
authors.forename: Chandima S K
authors.initials: CS
authors.lastname: Rajapakse
authors.affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.
authors.forename: Maryna
authors.initials: M
authors.lastname: Lisai
authors.affiliation: Unité Molécules de Communication et Adaptation des Microorganismes, (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle CNRS, Paris, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Deregnaucourt
authors.affiliation: Laboratory of Parasitology, Faculty of Pharmacy, UMR-MD3, Aix-Marseille University, Marseille, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Sinou
authors.affiliation: Laboratory of Parasitology, Faculty of Pharmacy, UMR-MD3, Aix-Marseille University, Marseille, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Latour
authors.affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.
authors.forename: Dipankar
authors.initials: D
authors.lastname: Roy
authors.affiliation: Unité Molécules de Communication et Adaptation des Microorganismes, (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle CNRS, Paris, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schrével
authors.affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Sánchez-Delgado
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002738:Chloroquine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004351:Drug Resistance / Q000187:drug effects*; D006801:Humans; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000378:metabolism*; D051381:Rats
chemical_list: D000962:Antimalarials; D002738:Chloroquine