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Title
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Synthesis of bicyclic **N**-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors
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Author
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Abstract
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| A series of bicyclic N-arylmethyl-substituted iminoribitols were synthesised and evaluated in vitro against T. vivax nucleoside hydrolase. The importance of the N-Asp40 interaction was confirmed and depends on an optimal pKa value, which can be influenced by substituents. The compounds were active inhibitors of nucleoside hydrolase (IAG-NH) and are inactive against human purine nucleoside phosphorylase. The purine metabolism of Trypanosoma and Leishmania spp. provides a good target in the search for new selective drugs. Bicyclic N-arylmethyl-substituted iminoribitols were developed as inhibitors of T. vivax nucleoside hydrolase, a key enzyme of the purine salvage pathway. The obtained results and structure-activity data confirmed our model for inhibitor binding with a hydrogen bond between a nitrogen atom of the nucleobase mimetic and the protonated Asp40 from the enzyme. This interaction depends on an optimal pKa value, which can be influenced by the electronic properties of the substituents. These compounds are potent, selective inhibitors of nucleoside hydrolase and are inactive toward human nucleoside phosphorylase. |
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Language
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English
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Source (journal)
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ChemMedChem. - Place of publication unknown
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Publication
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Place of publication unknown
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2009
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ISSN
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1860-7179
[print]
1860-7187
[online]
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DOI
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10.1002/CMDC.200800231
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Volume/pages
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4
:2
(2009)
, p. 249-260
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ISI
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000263803200014
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Full text (Publisher's DOI)
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