N-Arylmethyl substituted iminoribitol derivatives as inhibitors of a purine specific nucleoside hydrolase.
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.
Department of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, Antwerp B-2610, Belgium.
Annelies
A
Goeminne
Maya
M
Berg
Michael
M
McNaughton
Gunther
G
Bal
Georgiana
G
Surpateanu
Pieter
P
Van der Veken
Stijn
S
De Prol
Wim
W
Versées
Jan
J
Steyaert
Achiel
A
Haemers
Koen
K
Augustyns
D000818:Animals; D001224:Aspartic Acid; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D012255:Ribitol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry*; D016689:Trypanosoma vivax / Q000201:enzymology*; D014364:Tryptophan
D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; C089322:phenyliminoribitol; D001224:Aspartic Acid; D012255:Ribitol; D014364:Tryptophan; D009699:N-Glycosyl Hydrolases; C030681:purine nucleosidase