title: Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.
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.
authors.affiliation: WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde , 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.
authors.forename: Abedawn I
authors.initials: AI
authors.lastname: Khalaf
authors.forename: Judith K
authors.initials: JK
authors.lastname: Huggan
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Suckling
authors.forename: Colin L
authors.initials: CL
authors.lastname: Gibson
authors.forename: Kirsten
authors.initials: K
authors.lastname: Stewart
authors.forename: Federica
authors.initials: F
authors.lastname: Giordani
authors.forename: Michael P
authors.initials: MP
authors.lastname: Barrett
authors.forename: Pui Ee
authors.initials: PE
authors.lastname: Wong
authors.forename: Keri L
authors.initials: KL
authors.lastname: Barrack
authors.forename: William N
authors.initials: WN
authors.lastname: Hunter
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D014344:Trypanocidal Agents; D010088:Oxidoreductases; C085592:pteridine reductase