Prodrugs of Bisthiazolium Salts Are Orally Potent Antimalarials

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 Oct 20

PMID 15492221

Citations 37

Authors

Henri J Vial

Sharon Wein

Christine Farenc

Clemens Kocken

Olivier Nicolas

Marie Laure Ancelin

Francoise Bressolle

Alan Thomas

Michele Calas

Affiliations

Soon will be listed here.

Abstract

We created neutral antimalarial prodrugs that deliver bisthiazolium compounds with antimalarial activity in the nanomolar range. These drugs primarily affect early intraerythrocytic stages through rapid, nonreversible cytotoxicity. The compounds are suitable for both parenteral and oral use and plasma promotes rapid conversion of the prodrug into the drug. We demonstrate that very low doses offer protection in a murine model of malaria. The drugs show great potential for curing high parasitemia with short-course treatments. Oral administration of the TE3 prodrug completely cures Plasmodium cynomolgi infection in rhesus monkeys. The drugs specifically accumulate inside infected erythrocytes, block phosphatidylcholine biosynthesis, and interact with hemozoin. To our knowledge, this class of compounds represents one of the most potent antimalarials tested to date. These unique properties signal a promising future for this class of antimalarial.

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