Dihydro-alkylthio-benzyl-oxopyrimidines as Inhibitors of Reverse Transcriptase;Synthesis and Rationalization of the Biological Data on Both Wild-Type Enzyme and Relevant Clinical Mutants

摘要

A series of novel S-DABO analogues,characterized by different substitution patterns at positions 2,5,and 6 of the heterocyclic ring,were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1).Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays,with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC_(50wt) = 25 pM).The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach,leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.