N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.

TitleN-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.
Publication TypeJournal Article
Year of Publication2008
AuthorsGoeminne, A., M. Berg, M. McNaughton, G. Bal, G. Surpateanu, P. Van der Veken, S. De Prol, W. Versées, J. Steyaert, A. Haemers, and K. Augustyns
JournalBioorg Med Chem
Date Published2008 Jul 15
KeywordsAnimals, Aspartic Acid, Binding Sites, Computer Simulation, Enzyme Inhibitors, Hydrogen Bonding, Models, Molecular, N-Glycosyl Hydrolases, Protein Binding, Ribitol, Structure-Activity Relationship, Trypanocidal Agents, Trypanosoma vivax, Tryptophan

A key enzyme within the purine salvage pathway of parasites, nucleoside hydrolase, is proposed as a good target for new antiparasitic drugs. We have developed N-arylmethyl-iminoribitol derivatives as a novel class of inhibitors against a purine specific nucleoside hydrolase from Trypanosoma vivax. Several of our inhibitors exhibited low nanomolar activity, with 1,4-dideoxy-1,4-imino-N-(8-quinolinyl)methyl-d-ribitol (UAMC-00115, K(i) 10.8nM), N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.1nM), and N-(9-deazahypoxanthin-9-yl)methyl-1,4-dideoxy-1,4-imino-d-ribitol (K(i) 4.4nM) being the three most active compounds. Docking studies of the most active inhibitors revealed several important interactions with the enzyme. Among these interactions are aromatic stacking of the nucleobase mimic with two Trp-residues, and hydrogen bonds between the hydroxyl groups of the inhibitors and amino acid residues in the active site. During the course of these docking studies we also identified a strong interaction between the Asp40 residue from the enzyme and the inhibitor. This is an interaction which has not previously been considered as being important.

Alternate JournalBioorg. Med. Chem.
PubMed ID18571422