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JAC Advance Access originally published online on April 14, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1043-1054; doi:10.1093/jac/dkl104
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Reviews

The past, present and future of antifolates in the treatment of Plasmodium falciparum infection

Alexis Nzila1,–3,*

1 Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program PO Box 230, 80108, Kilifi, Kenya 2 Department of Pharmacology and Therapeutics, University of Liverpool Liverpool L69 3BX, UK 3 Liverpool School of Tropical Medicine Pembroke Place, Liverpool L53QA5, UK

*Correspondence address. Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, PO Box 230, 80108, Kilifi, Kenya. Tel: +254-41-522535/522063/525043; Fax: +254-41-522390; E-mail: anzila{at}kilifi.mimcom.net

Chemotherapy remains the most important means of controlling malaria, one of the deadliest infectious parasitic diseases in the world. Antimalarial antifolates have been central for prophylaxis and treatment of malaria. This drug family was discovered in the 1940s, during the Second World War, and molecules that are currently in clinical use were discovered at that time. Since the 1940s, no new antimalarial antifolates have been developed that have reached Phase I/II stages. Limited work has been carried out to exploit the inhibition of the malaria folate pathway as a means of discovering new drugs. In this review, work carried out on antimalarial antifolates since the 1940s up to the present time is discussed in terms of discovery, clinical use, mode of action and mechanism of resistance. New concepts have been presented to improve antimalarial antifolate in vivo efficacy and to identify potent new antifolate agents.

Keywords: malaria , antimalarials , folate , dihydrofolate reductase , dihydropteroate synthase


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