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

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Chowdhury SF, Villamor VB, Guerrero RH, Leal I, Brun R, Croft SL, Goodman JM, Maes L, Ruiz-Perez LM, Pacanowska DG, Gilbert IH

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

J Med Chem. 1999 Oct 21;42(21):4300-12.

PubMed ID
10543874 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PyrimethamineDihydrofolate reductaseKi (nM)98N/AN/ADetails
PyrimethamineDihydrofolate reductaseKi (nM)120N/AN/ADetails
PyrimethamineDihydrofolate reductaseKi (nM)250N/AN/ADetails
PyrimethamineDihydrofolate reductaseKi (nM)11N/AN/ADetails
TrimethoprimDihydrofolate reductaseKi (nM)1000N/AN/ADetails
TrimethoprimDihydrofolate reductaseKi (nM)10N/AN/ADetails
TrimethoprimDihydrofolate reductaseKi (nM)1380N/AN/ADetails
TrimethoprimDihydrofolate reductaseKi (nM)120N/AN/ADetails