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

Khalaf, A. I., Huggan, J. K., Suckling, C. J., Gibson, C. L., Stewart, K., Giordani, F. , Barrett, M. P. , Wong, P. E., Barrack, K. L. and Hunter, W. N. (2014) Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1. Journal of Medicinal Chemistry, 57(15), pp. 6479-6494. (doi:10.1021/jm500483b)

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Abstract

The treatment of Human African trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important; 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 Trypanosoma 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. Eight 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Giordani, Dr Federica and Wong, Dr Pui Ee and Barrett, Professor Michael
Authors: Khalaf, A. I., Huggan, J. K., Suckling, C. J., Gibson, C. L., Stewart, K., Giordani, F., Barrett, M. P., Wong, P. E., Barrack, K. L., and Hunter, W. N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN:0022-2623
ISSN (Online):1520-4804
Copyright Holders:Copyright © 2014 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 57(15):6479-6494
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544283Antiparasitic pyrrolopyrimidinesMichael BarrettMedical Research Council (MRC)G0901426/1III - PARASITOLOGY