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Antimicrobial Agents and Chemotherapy, September 2005, p. 3652-3657, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3652-3657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

2,4-Diaminopteridine-Based Compounds as Precursors for De Novo Synthesis of Antifolates: a Novel Class of Antimalarials

Eunice Nduati,1 Sonya Hunt,4 Eddy M. Kamau,1 and Alexis Nzila1,2,3*

Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Wellcome Trust Research Laboratories, P.O. Box 43640, Nairobi, Kenya,1 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 3BX, United Kingdom,2 Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L53QA, United Kingdom,3 University of Washington, Department of Genome Sciences, Box 357730, Seattle, WA 98195-77304

Received 4 January 2005/ Returned for modification 8 April 2005/ Accepted 1 June 2005

We have tested the hypothesis that 2,4-diamino-6-hydroxymethyl-pteridine (DAP), 2,4-diaminopteroic acid (DAPA), and 2,4 diamino-N10-methyl-pteroic acid (DAMPA) could be converted into aminopterin (from DAP and DAPA) and methotrexate (from DAMPA), both of which are potent inhibitors of dihydrofolate reductase, a proven drug target for Plasmodium falciparum. DAP, DAPA, and DAMPA inhibited parasite growth in the micromolar range; DAMPA was the most active, with 50% inhibitory concentrations in vitro of 446 ng/ml against the antifolate-sensitive strain and 812 ng/ml against the highly resistant strain under physiological folate conditions. DAMPA potentiates the activity of the sulfone dapsone, an inhibitor of dihydropteroate synthase, but not that of chlorcycloguanil, a known inhibitor of dihydrofolate reductase (DHFR). Experiments with a Saccharomyces cerevisiae strain dependent upon the P. falciparum DHFR enzyme showed that DHFR is a target of DAMPA in that system. We hypothesize that DAMPA is converted to methotrexate by the parasite dihydrofolate synthase, which explains the synergy of DAMPA with dapsone but not with chlorcycloguanil. This de novo synthesis will not occur in the host, since it lacks the complete folate pathway. If this hypothesis holds true, the de novo synthesis of the toxic compounds could be used as a framework for the search for novel potent antimalarial antifolates.

* Corresponding author. Mailing address: Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, Wellcome Trust Research Laboratories, P.O. Box 43640, GPO 00100, Nairobi, Kenya. Phone: 254-2-2710672. Fax: 254-2-2711673. E-mail: anzila{at}wtnairobi.mimcom.net.

Antimicrobial Agents and Chemotherapy, September 2005, p. 3652-3657, Vol. 49, No. 9
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.9.3652-3657.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Aboge, G. O., Jia, H., Terkawi, M. A., Goo, Y.-K., Nishikawa, Y., Sunaga, F., Namikawa, K., Tsuji, N., Igarashi, I., Suzuki, H., Fujisaki, K., Xuan, X. (2008). Cloning, Expression, and Characterization of Babesia gibsoni Dihydrofolate Reductase-Thymidylate Synthase: Inhibitory Effect of Antifolates on Its Catalytic Activity and Parasite Proliferation. Antimicrob. Agents Chemother. 52: 4072-4080 [Abstract] [Full Text]  
  • Nzila, A. (2006). The past, present and future of antifolates in the treatment of Plasmodium falciparum infection. J Antimicrob Chemother 57: 1043-1054 [Abstract] [Full Text]  


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