Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.
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.
Caldarelli
Sergio A
SA
Institut des Biomolécules Max Mousseron, UMR CNRS, Université Montpellier, France.
Boisbrun
Michel
M
Alarcon
Karine
K
Hamzé
Abdallah
A
Ouattara
Mahama
M
Salom-Roig
Xavier
X
Maynadier
Marjorie
M
Wein
Sharon
S
Peyrottes
Suzanne
S
Pellet
Alain
A
Calas
Michèle
M
Vial
Henri
H
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*
D000962:Antimalarials; D011355:Prodrugs; D012492:Salts; D013844:Thiazoles