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Research Article Open Access
Amodiaquine (AQ), marketed as a combination with Artesunate and prescribed to millions of patients, is one of the most active anti-malarial 4-aminoquinoline. Its major drawback is its weak metabolic stability. Its metabolism is believed to generate inactive or hepatotoxic derivatives. Recently a new series of amodiaquine analogs, in which the hydroxyl group at the 4’ position was replaced by various amino groups, was designed. Among them, compounds bearing a N-methylpiperazino (PM6280) or a morpholino group (PM6577), provided low nanomolar activities upon a panel of chloroquine-sensitive and chloroquine-resistant strains such as F32 and K1, low cytotoxicity, inhibition of hematin polymerization and in vivo efficiency comparable to AQ.In this work, physicochemical properties and permeability profiles of PM6280 and PM6577were evaluated as well as ADME properties related to oral delivery for a potential preclinical phase. Both compounds were subjected to metabolic studies in order to evaluate whether they avoid the excessive metabolism and formation of toxic derivatives observed with AQ. Putative metabolites were identified. The introduction of a heterocyclic amine at the 4’-position together with the replacement of the diethylamino side chain with a pyrrolidino group greatly improved the metabolic stability of this family of compounds.