Publication
Title
Synthesis of bicyclic **N**-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors
Author
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.
Language
English
Source (journal)
ChemMedChem. - Place of publication unknown
Publication
Place of publication unknown : 2009
ISSN
1860-7179 [print]
1860-7187 [online]
DOI
10.1002/CMDC.200800231
Volume/pages
4 :2 (2009) , p. 249-260
ISI
000263803200014
Full text (Publisher's DOI)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 12.03.2009
Last edited 28.08.2024
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