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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• 作者：Claudia Mugnaini ; Maddalena Alongi ; Andrea Togninelli ; Harsukh Gevariya ; Antonella Brizzi ; Fabrizio Manetti ; Cesare Bernardini ; Lucilla Angeli ; Andrea Tafi ; Luca Bellucci ; Federico Corelli ; Silvio Mas
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：December 27, 2007
• 年：2007
• 卷：50
• 期：26
• 页码：6580 - 6595
• 全文大小：1230K
• 年卷期：v.50,no.26(December 27, 2007)
• ISSN：1520-4804

文摘

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.