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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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Caldarelli SA,Boisbrun M,Alarcon K,Hamzé A,Ouattara M,Salom-Roig X,Maynadier M,Wein S,Peyrottes S,Pellet A,Calas M,Vial H

doi

10.1016/j.bmcl.2010.05.001

subject

Has Abstract

pub_date

2010-07-01 00:00:00

pages

3953-6

issue

13

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(10)00628-1

journal_volume

20

pub_type

杂志文章

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