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

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• 作者：Sergio A. Caldarelli ; Matthieu Hamel ; Jean-Fr茅d茅ric Duckert ; Mahama Ouattara ; Mich猫le Calas ; Marjorie Maynadier ; Sharon Wein ; Christian P茅rigaud ; Alain Pellet ; Henri J. Vial ; Suzanne Peyrottes
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4619-4628
• 全文大小：389K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

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.