Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities - Archive ouverte HAL
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2012

Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities

Résumé

We report herein the design, synthesis, and biological screening of a series of 15 disulfide prodrugs as precursors of albitiazolium bromide (T3/SAR97276, compound 1), a choline analogue which is currently being evaluated in clinical trials (phase II) for severe malaria. The corresponding prodrugs are expected to revert back to the active bis-thiazolium salt through an enzymatic reduction of the disulfide bond. To enhance aqueous solubility of these prodrugs, an amino acid residue (valine or lysine) or a phosphate group was introduced on the thiazolium side chain. Most of the novel derivatives exhibited potent in vitro antimalarial activity against P. falciparum. After oral administration, the cyclic disulfide prodrug 8 showed the best improvement of oral efficacy in comparison to the parent drug.

Domaines

Chimie organique
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Dates et versions

hal-00712623 , version 1 (27-06-2012)

Identifiants

Citer

Sergio Caldarelli, Matthieu Hamel, Jean-Frédéric Duckert, Mahama Ouattara, Michèle Calas, et al.. Disulfide Prodrugs of Albitiazolium (T3/SAR97276): Synthesis and Biological Activities. Journal of Medicinal Chemistry, 2012, 55, pp.4619-4628. ⟨10.1021/jm3000328⟩. ⟨hal-00712623⟩
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