Synthesis of bicyclic N-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors.

TitleSynthesis of bicyclic N-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors.
Publication TypeJournal Article
Year of Publication2009
AuthorsBerg, M., G. Bal, A. Goeminne, P. Van der Veken, W. Versées, J. Steyaert, A. Haemers, and K. Augustyns
JournalChemMedChem
Volume4
Issue2
Pagination249-60
Date Published2009 Feb
ISSN1860-7187
KeywordsEnzyme Inhibitors, Magnetic Resonance Spectroscopy, Models, Molecular, N-Glycosyl Hydrolases, Ribitol, Spectrometry, Mass, Electrospray Ionization
Abstract

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 pK(a) 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.

DOI10.1002/cmdc.200800231
Alternate JournalChemMedChem
PubMed ID19115304