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J Med Chem. 2012 May 24;55(10):4619-28. doi: 10.1021/jm3000328. Epub 2012 May 16.

Disulfide prodrugs of albitiazolium (T3/SAR97276): synthesis and biological activities.

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  • 1Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Université Montpellier 2 , cc 1705, place E. Bataillon, 34095 Montpellier, France.

Abstract

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.

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