Synthesis of Bicyclic N-Arylmethyl-Substituted Iminoribitol Derivatives as Selective Nucleoside Hydrolase Inhibitors

摘要

The purine metabolism of Trypanosoma and Leishmania spp. provides a good target in the search for new selective drugs. Bi-cyclic 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-ac-tivity data confirmed our model for inhibitor binding with a hy-drogen bond between a nitrogen atom of the nudeobase mimetic and the protonated Asp40 from the enzyme. This interaction depends on an optimal pK_α 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.