title: 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.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-UM1&2, Université Montpellier 2 , cc 1705, place E. Bataillon, 34095 Montpellier, France.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Caldarelli
authors.forename: Matthieu
authors.initials: M
authors.lastname: Hamel
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Duckert
authors.forename: Mahama
authors.initials: M
authors.lastname: Ouattara
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maynadier
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Christian
authors.initials: C
authors.lastname: Périgaud
authors.forename: Alain
authors.initials: A
authors.lastname: Pellet
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C499114:1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane; C574760:3,20-bis(2-(acetoxy)ethyl)-4,19-dimethyl-1,2-dithia-5,18-diazacycloicosa-3,19-diene-5,18-dicarbaldehyde; D000962:Antimalarials; D004220:Disulfides; D011355:Prodrugs; D013844:Thiazoles