Design, synthesis, and evaluation of inhibitors of trypanosomal and leishmanial dihydrofolate reductase

Shafinaz F. Chowdhury, Victor Bernier Villamor, Ramon Hurtado Guerrero, Isabel Leal, Reto Brun, Simon L. Croft, Jonathan M. Goodman, Louis Maes, Luis M. Ruiz-Perez, Dolores Gonzalez Pacanowska, Ian H. Gilbert

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    Abstract

    This paper concerns the design, synthesis, and evaluation of inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Initially study was made of the structures of the leishmanial and human enzyme active sites to see if there were significant differences which could be exploited for selective drug design. Then a series of compounds were synthesized based on 5-benzyl-2,4-diaminopyrimidines. These compounds were assayed against the protozoan and human enzymes and showed selectivity for the protozoan enzymes. The structural data was then used to rationalize the enzyme assay data. Compounds were also tested against the clinically relevant forms of the intact parasite. Activity was seen against the trypanosomes for a number of compounds. The compounds were in general less active against Leishmania. This latter result may be due to uptake problems. Two of the compounds also showed some in vivo activity in a model of African trypanosomiasis.

    Original languageEnglish
    Pages (from-to)4300-4312
    Number of pages13
    JournalJournal of Medicinal Chemistry
    Volume42
    Issue number21
    DOIs
    Publication statusPublished - Oct 1999

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