Abstract
A molecular hybridization approach is a powerful tool in the design of new molecules with improved affinity and efficacy. In this context, a series of diarylpyrimidine-quinolone hybrids were synthesized and evaluated against both wt HIV-1 and mutant viral strains. The most active hybrid 5a displayed an EC50 value of 0.28±0.07μM against HIV-1 IIIB. A couple of enzyme-based assays clearly pinpoint a RT-targeted mechanism of action. Docking studies revealed that these hybrids could be well located in the NNIBP of HIV-1 RT despite the bulky and polar properties of a quinolone 3-carboxylic acid moiety in the molecules.
Keywords:
Anti-HIV; Diarylpyrimidine–quinolone hybrids; HIV-1 reverse transcriptase; Integrase.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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 / pharmacology*
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Binding Sites
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Cell Line
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Drug Design
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Granulocyte Precursor Cells / drug effects
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Granulocyte Precursor Cells / pathology
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Granulocyte Precursor Cells / virology
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HIV Reverse Transcriptase / antagonists & inhibitors
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HIV-1 / drug effects*
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HIV-1 / enzymology
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HIV-1 / growth & development
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Humans
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Models, Molecular
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Molecular Docking Simulation
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Pyrimidines / chemical synthesis
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Pyrimidines / pharmacology*
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Quinolones / chemical synthesis
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Quinolones / pharmacology*
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Tetradecanoylphorbol Acetate / pharmacology
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Virus Latency / drug effects
Substances
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Anti-HIV Agents
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Pyrimidines
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Quinolones
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase
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Tetradecanoylphorbol Acetate