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PDBsum entry 4clh
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Oxidoreductase
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PDB id
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4clh
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References listed in PDB file
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Key reference
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Title
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Structure-Based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1.
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Authors
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A.I.Khalaf,
J.K.Huggan,
C.J.Suckling,
C.L.Gibson,
K.Stewart,
F.Giordani,
M.P.Barrett,
P.E.Wong,
K.L.Barrack,
W.N.Hunter.
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Ref.
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J Med Chem, 2014,
57,
6479-6494.
[DOI no: ]
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PubMed id
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Abstract
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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.
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