Synthesis and Testing of 5-Benzyl-2,4-diaminopyrimidines as Potential Inhibitors of Leishmanial and Trypanosomal Dihydrofolate Reductase |
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Authors: | Shafinaz F Chowdhury Ramon Hurtado Guerrero Reto Brun Luis M Ruiz-Perez Dolores Gonzalez Pacanowska Ian H Gilbert |
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Institution: | 1. Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK;2. Instituto de Parasitologia y Biomedicina, Consejo Superior de Investigaciones Cientificas, C/Ventanilla 11, 18001- Granada, Spain;3. Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland |
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Abstract: | Dihydrofolate reductase is a drug target that has not been thoroughly investigated in leishmania and trypanosomes. Work has previously shown that 5-benzyl-2,4-diaminopyrimidines are selective inhibitors of the leishmanial and trypanosome enzymes. Modelling predicted that alkyl/aryl substitution on the 6-position of the pyrimidine ring should increase enzyme activity of 5-benzyl-2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Various compounds were prepared and evaluated against both the recombinant enzymes and the intact organisms. The presence of a substituent had a small or negative effect on activity against the enzyme or intact parasites compared to unsubstituted compounds. |
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Keywords: | Dihydrofolate Reductase Trypanosoma Brucei Trypanosoma Cruzi Leishmania |
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