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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

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journal contribution
posted on 27.12.2007, 00:00 by Claudia Mugnaini, Maddalena Alongi, Andrea Togninelli, Harsukh Gevariya, Antonella Brizzi, Fabrizio Manetti, Cesare Bernardini, Lucilla Angeli, Andrea Tafi, Luca Bellucci, Federico Corelli, Silvio Massa, Giovanni Maga, Alberta Samuele, Marcella Facchini, Imma Clotet-Codina, Mercedes Armand-Ugón, José A. Esté, Maurizio Botta
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 (EC50wt = 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.