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Antimicrobial Agents and Chemotherapy, January 2001, p. 187-195, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.187-195.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Efficacies of Lipophilic Inhibitors of Dihydrofolate Reductase against Parasitic Protozoa

Hollis Lau,1 Jill T. Ferlan,1 Victoria Hertle Brophy,2 Andre Rosowsky,3 and Carol Hopkins Sibley1,*

Department of Genetics, University of Washington, Seattle, Washington 98195-73601; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195-73502; and Dana-Farber Cancer Institute and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 021153

Received 3 July 2000/Returned for modification 11 September 2000/Accepted 5 October 2000

Competitive inhibitors of dihydrofolate reductase (DHFR) are used in chemotherapy or prophylaxis of many microbial pathogens, including the eukaryotic parasites Plasmodium falciparum and Toxoplasma gondii. Unfortunately, point mutations in the DHFR gene can confer resistance to inhibitors specific to these pathogens. We have developed a rapid system for testing inhibitors of DHFRs from a variety of parasites. We replaced the DHFR gene from the budding yeast Saccharomyces cerevisiae with the DHFR-coding region from humans, P. falciparum, T. gondii, Pneumocystis carinii, and bovine or human-derived Cryptosporidium parvum. We studied 84 dicyclic and tricyclic 2,4-diaminopyrimidine derivatives in this heterologous system and identified those most effective against the DHFR enzymes from each of the pathogens. Among these compounds, six tetrahydroquinazolines were effective inhibitors of every strain tested, but they also inhibited the human DHFR and were not selective for the parasites. However, two quinazolines and four tetrahydroquinazolines were both potent and selective inhibitors of the P. falciparum DHFR. These compounds show promise for development as antimalarial drugs.

* Corresponding author. Mailing address: Department of Genetics, Box 357360, University of Washington, Seattle, WA 98195-7360. Phone: (206) 685-9378. Fax: (206) 543-0754. E-mail: sibley{at}genetics.washington.edu.

Antimicrobial Agents and Chemotherapy, January 2001, p. 187-195, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.187-195.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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