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

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.

• Authors: Sergio A Caldarelli, Matthieu Hamel, Jean-Frédéric Duckert, Mahama Ouattara, Michèle Calas, Marjorie Maynadier, Sharon Wein, Christian Périgaud, Alain Pellet, Henri J Vial, Suzanne Peyrottes
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 10 Pg. 4619-28 (May 24 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22591034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane
• 3,20-bis(2-(acetoxy)ethyl)-4,19-dimethyl-1,2-dithia-5,18-diazacycloicosa-3,19-diene-5,18-dicarbaldehyde
• Antimalarials
• Disulfides
• Prodrugs
• Thiazoles

Topics

• Animals
• Antimalarials (chemical synthesis, chemistry, pharmacology)
• Disulfides (chemical synthesis, chemistry, pharmacology)
• Malaria (drug therapy)
• Mice
• Plasmodium falciparum (drug effects)
• Prodrugs (chemical synthesis, chemistry, pharmacology)
• Stereoisomerism
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)