Exploration of potential prodrug approach of the bis-thiazolium salts T and T4 for orally delivered antimalarials.

S. Caldarelli (1) , Michel Boisbrun (1) , Karine Alarcon (1) , Abdallah Hamzé (1) , Mahama Ouattara (1) , Xavier Salom-Roig (1) , Marjorie Maynadier (2) , Sharon Wein (2) , Suzanne Peyrottes (1) , Alain Pellet (3) , Michèle Calas (1) , Henri J Vial (2)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 DIMNP - Dynamique des interactions membranaires normales et pathologiques
3 Sanofi-Aventis R&D

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 IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Domaines: Chimie

S. Caldarelli, Michel Boisbrun, Karine Alarcon, Abdallah Hamzé, Mahama Ouattara, et al.. Exploration of potential prodrug approach of the bis-thiazolium salts T and T4 for orally delivered antimalarials.. Bioorganic and Medicinal Chemistry Letters, 2010, 20, pp.3953-3956. ⟨10.1016/j.bmcl.2010.05.001⟩. ⟨hal-00501627⟩