Structure based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

Abedawn I Khalaf, Judith Huggan, Colin J Suckling, Colin L Gibson, Kirsten Stewart, Federica Giordani, Michael P. Barrett, Pui Ee Wong, Keri L Barrack, William N Hunter

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development.
LanguageEnglish
Pages6479-6494
Number of pages6
JournalJournal of Medicinal Chemistry
Volume57
Issue number15
Early online date9 Jul 2014
DOIs
Publication statusPublished - 2014

Fingerprint

Antiparasitic Agents
African Trypanosomiasis
Trypanosoma
Africa South of the Sahara
Poisons
Enzymes
pyrrolopyrimidine
pteridine reductase
Health
Pyrrolo(2,3-d)pyrimidine

Keywords

  • sleeping sickness
  • trypanosoma brucei
  • pteridine reductase 1
  • structure-based design
  • pyrrolo[2,3-d]pyrimidines

Cite this

Khalaf, Abedawn I ; Huggan, Judith ; Suckling, Colin J ; Gibson, Colin L ; Stewart, Kirsten ; Giordani, Federica ; Barrett, Michael P. ; Wong, Pui Ee ; Barrack, Keri L ; Hunter, William N. / Structure based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 15. pp. 6479-6494.
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Khalaf, AI, Huggan, J, Suckling, CJ, Gibson, CL, Stewart, K, Giordani, F, Barrett, MP, Wong, PE, Barrack, KL & Hunter, WN 2014, 'Structure based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1' Journal of Medicinal Chemistry, vol. 57, no. 15, pp. 6479-6494. https://doi.org/10.1021/jm500483b

Structure based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1. / Khalaf, Abedawn I; Huggan, Judith; Suckling, Colin J; Gibson, Colin L; Stewart, Kirsten; Giordani, Federica ; Barrett, Michael P.; Wong, Pui Ee; Barrack, Keri L ; Hunter, William N.

In: Journal of Medicinal Chemistry, Vol. 57, No. 15, 2014, p. 6479-6494.

Research output: Contribution to journalArticle

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