2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase

Didier Pez, Isabel Leal, Fabio Zuccotto, Cyrille Boussard, Reto Brun, Simon L. Croft, Vanessa Yardley, Luis M. Ruiz Perez, Dolores Gonzalez Pacanowska, Ian H. Gilbert (Lead / Corresponding author)

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

This paper describes the synthesis of 4'-substituted and 3,4'-disubstituted 5-benzyl-2,4-diaminopyrimidines as selective inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Compounds were then assayed against the recombinant parasite and human enzymes. Some of the compounds showed good activity. They were also tested against the intact parasites using in vitro assays. Good activity was found against Trypanosoma cruzi, moderate activity against Trypanosoma brucei and Leishmania donovani. Molecular modeling was undertaken to explain the results. The leishmanial enzyme was found to have a more extensive lipophilic binding region in the active site than the human enzyme. Compounds which bound within the pocket showed the highest selectivity. (C) 2003 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)4693-4711
Number of pages19
JournalBioorganic & Medicinal Chemistry
Volume11
Issue number22
Early online date22 Sep 2003
DOIs
Publication statusPublished - 3 Nov 2003

Keywords

  • Animals
  • Binding sites
  • Cells, Cultured
  • Folic acid antagonists
  • Humans
  • Leishmania donovani
  • Leishmania major
  • Macrophages, Peritoneal
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Muscle, Skeletal
  • Pyrimidines
  • Rats
  • Recombinant proteins
  • Structure-activity relationship
  • Tetrahydrofolate dehydrogenase
  • Trypanocidal agents
  • Trypanosoma brucei rhodesiense
  • Trypanosoma cruzi
  • Journal article

Cite this

Pez, D., Leal, I., Zuccotto, F., Boussard, C., Brun, R., Croft, S. L., Yardley, V., Perez, L. M. R., Pacanowska, D. G., & Gilbert, I. H. (2003). 2,4-diaminopyrimidines as inhibitors of Leishmanial and Trypanosomal dihydrofolate reductase. Bioorganic & Medicinal Chemistry, 11(22), 4693-4711. https://doi.org/10.1016/j.bmc.2003.08.012