title: Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.
abstract: We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR CNRS, Université Montpellier, France.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Caldarelli
authors.forename: Michel
authors.initials: M
authors.lastname: Boisbrun
authors.forename: Karine
authors.initials: K
authors.lastname: Alarcon
authors.forename: Abdallah
authors.initials: A
authors.lastname: Hamzé
authors.forename: Mahama
authors.initials: M
authors.lastname: Ouattara
authors.forename: Xavier
authors.initials: X
authors.lastname: Salom-Roig
authors.forename: Marjorie
authors.initials: M
authors.lastname: Maynadier
authors.forename: Sharon
authors.initials: S
authors.lastname: Wein
authors.forename: Suzanne
authors.initials: S
authors.lastname: Peyrottes
authors.forename: Alain
authors.initials: A
authors.lastname: Pellet
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Henri
authors.initials: H
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008288:Malaria / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010961:Plasmodium / Q000187:drug effects*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012492:Salts / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D011355:Prodrugs; D012492:Salts; D013844:Thiazoles