title: Potent antimalarial activity of 2-aminopyridinium salts, amidines, and guanidines.
abstract: We describe the design, synthesis, and antimalarial activity of 60 bis-tertiary amine, bis-2(1 H)-imino-heterocycle, bis-amidine, and bis-guanidine series. Bis-tertiary amines with a linker from 12 to 16 methylene groups were active against the in vitro growth of Plasmodium falciparum within the 10 (-6)-10 (-7) M concentration range. IC 50 decreased by 2 orders of magnitude for bis-2-aminopyridinium salts, bis-amidines, and bis-guanidines (27 compounds with IC 50 < 10 nM). Increasing the alkyl chain length from 6 to 12 methylene groups led to increased activity, while beyond this antimalarial activity decreased. Antimalarial activities appear to be strictly related to the basicity of the cationic head with an optimal p K a over 12.5. Maximal activity occurs for bis-2-aminopyridinium, two C-duplicated bis-amidines, and three bis-guanidines, with IC 50 values lower than 1 nM. In comparison to similar quaternary ammonium salts, amidinium compounds have distinct structural requirements for antimalarial activity and likely additional binding opportunities on account of their hydrogen-bond-forming properties.
authors.affiliation: Institut des Biomolécules Max Mousseron, CNRS UMR 5247, Université Montpellier 1, Faculté de Pharmacie, 15, Avenue C. Flahault, BP 14491, 34093 Montpellier Cedex 5, France. michele.calas@univ-montp2.fr
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Mahama
authors.initials: M
authors.lastname: Ouattara
authors.forename: Gilles
authors.initials: G
authors.lastname: Piquet
authors.forename: Zyta
authors.initials: Z
authors.lastname: Ziora
authors.forename: Y
authors.initials: Y
authors.lastname: Bordat
authors.forename: Marie L
authors.initials: ML
authors.lastname: Ancelin
authors.forename: Roger
authors.initials: R
authors.lastname: Escale
authors.forename: Henri
authors.initials: H
authors.lastname: Vial
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000578:Amidines; D000631:Aminopyridines; D000962:Antimalarials; D006146:Guanidines; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds