Title
Synthesis of bicyclic **N**-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors Synthesis of bicyclic **N**-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Publication type
article
Publication
,
Subject
Chemistry
Pharmacology. Therapy
Source (journal)
ChemMedChem. - Place of publication unknown
Volume/pages
4(2009) :2 , p. 249-260
ISSN
1860-7179
1860-7187
ISI
000263803200014
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
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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