title: Comparative analysis of in vitro rat liver metabolism of the antimalarial primaquine and a derived imidazoquine.
abstract: The present study provides proof-of-concept regarding the expectedly high enzymatic stability of primaquinederived imidazolidin-4-ones, imidazoquines, formerly developed as alternatives to the parent antimalarial with potentially improved oral bioavailability [J. Med. Chem., 2009, 52, 7800-7807]. This study provides relevant experimental evidence on the remarkably low propensity of imidazoquines to undergo metabolic conversions mediated by rat liver enzymes. This, together with favourable key ADME parameters previously predicted for these compounds [Bioorg. Med. Chem. Lett. 2009, 19, 6914-6917], and proven lack of acute toxicity in mice, further reinforces the role of imidazoquines as reference leads for the development of novel primaquine surrogates. This is a particularly relevant issue in the present status of malaria chemotherapy worldwide, where primaquine remains the sole drug in clinical use able to block transmission between infected persons and the insect vector and to effectively act on liver-stage parasite forms, including hypnozoites.
authors.affiliation: Centro de Investigacao em Quimica da Universidade do Porto, Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, Rua do Campo Alegre, 687, 4169-007 Porto, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Vale
authors.forename: Iva
authors.initials: I
authors.lastname: Fernandes
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
authors.forename: Nuno
authors.initials: N
authors.lastname: Mateus
authors.forename: Paula
authors.initials: P
authors.lastname: Gomes
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D048289:Imidazolidines / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011319:Primaquine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D051381:Rats
chemical_list: D000962:Antimalarials; D048289:Imidazolidines; D011319:Primaquine