title: Synthesis and antimalarial activity of new amino analogues of amodiaquine.
abstract: Amodiaquine remains one of the most prescribed antimalarial 4-aminoquinoline. To assess the importance of the 4'-hydroxyl group and subsequent hydrogen bond in the antimalarial activity of amodiaquine (AQ), a series of new analogues in which this functionality was replaced by various amino groups was synthesized. The incorporation of a 3'-pyrrolidinamino group instead of the 3'-diethylamino function of AQ allowed the development of a parallel series of amopyroquine derivatives. The compounds were screened against both chloroquine (CQ)-sensitive and -resistant strains of Plasmodium falciparum and their cytotoxicity evaluated upon the MRC5 cell line. Antimalarial activity in a low nanomolar range was recorded showing that the 4'-hydroxy function can be successfully replaced by various amino substituents in terms of activity without any influence of the level of CQ-resistance of the strains. Furthermore the ability of the compounds to inhibit beta-hematin formation was measured in order to discuss the mechanism of action of these new compounds. Compounds 7d and 8d exhibit a high selectivity index and may be considered as promising leads for further development.
authors.affiliation: UMR CNRS 8161 - Universités de Lille I & II - Institut Pasteur de Lille, 1 rue du Professeur Calmette, B.P. 447, 59021 Lille cedex, France.
authors.forename: E
authors.initials: E
authors.lastname: Paunescu
authors.forename: S
authors.initials: S
authors.lastname: Susplugas
authors.forename: E
authors.initials: E
authors.lastname: Boll
authors.forename: R A
authors.initials: RA
authors.lastname: Varga
authors.forename: E
authors.initials: E
authors.lastname: Mouray
authors.forename: P
authors.initials: P
authors.lastname: Grellier
authors.forename: P
authors.initials: P
authors.lastname: Melnyk
mesh_terms: D000588:Amines / Q000737:chemistry*; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000962:Antimalarials; D011759:Pyrrolidines; D000655:Amodiaquine