title: Incorporation of a 3-(2,2,2-trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities.
abstract: In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC₅₀ values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.
authors.affiliation: Equipe "Biomolécules Fluorées", Chimie Organique Bioorganique Réactivité et Analyses-COBRA, Institut de Recherche en Chimie Organique Fine de Rouen-IRCOF, UMR CNRS 6014, Université et Institut National des Sciences Appliquées-INSA de Rouen, F-76821 Mont Saint Aignan Cedex, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Cornut
authors.forename: Hugues
authors.initials: H
authors.lastname: Lemoine
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Kanishchev
authors.forename: Etsuji
authors.initials: E
authors.lastname: Okada
authors.forename: Florian
authors.initials: F
authors.lastname: Albrieux
authors.forename: Abdoul Habib
authors.initials: AH
authors.lastname: Beavogui
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Bienvenu
authors.forename: Stéphane
authors.initials: S
authors.lastname: Picot
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Bouillon
authors.forename: Maurice
authors.initials: M
authors.lastname: Médebielle
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D007769:Lactams; D002738:Chloroquine