Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Cell Line
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HIV Reverse Transcriptase / chemistry
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism*
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HIV-1 / drug effects*
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HIV-1 / enzymology
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Humans
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Models, Molecular
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Mutation
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Quantitative Structure-Activity Relationship
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Recombinant Proteins / chemistry
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / pharmacology
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Sulfides / chemical synthesis*
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Sulfides / chemistry
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Sulfides / pharmacology
Substances
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Anti-HIV Agents
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Pyrimidines
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Recombinant Proteins
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Reverse Transcriptase Inhibitors
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Sulfides
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase