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Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials
Authors:Sergio A Caldarelli  Michel Boisbrun  Karine Alarcon  Abdallah Hamzé  Mahama Ouattara  Xavier Salom-Roig  Marjorie Maynadier  Sharon Wein  Suzanne Peyrottes  Alain Pellet  Michèle Calas  Henri Vial
Institution:1. Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France;2. Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université de Montpellier 2, CC 107, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France;3. Sanofi-Aventis, Research & Development, 195 route d’Espagne, BP 13669, 31036 Toulouse Cedex 1, France
Abstract:We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC50 lower than 7 nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC50 = 2.2 and 1.8 nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3 mg/kg.
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