Title | Synthesis of bicyclic N-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Berg, M., G. Bal, A. Goeminne, P. Van der Veken, W. Versées, J. Steyaert, A. Haemers, and K. Augustyns |
Journal | ChemMedChem |
Volume | 4 |
Issue | 2 |
Pagination | 249-60 |
Date Published | 2009 Feb |
ISSN | 1860-7187 |
Keywords | Enzyme 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. |
DOI | 10.1002/cmdc.200800231 |
Alternate Journal | ChemMedChem |
PubMed ID | 19115304 |
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