Synthesis of bicyclic N-arylmethyl-substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors.
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.
Berg
Maya
M
Department of Medicinal Chemistry, University of Antwerp, Belgium.
Bal
Gunther
G
Goeminne
Annelies
A
Van der Veken
Pieter
P
Versées
Wim
W
Steyaert
Jan
J
Haemers
Achiel
A
Augustyns
Koen
K
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors*; D012255:Ribitol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization
D004791:Enzyme Inhibitors; D012255:Ribitol; D009699:N-Glycosyl Hydrolases