Abstract
The pathway by which HIV-1 enters host cells is a prime target for novel drug discovery because of its critical role in the life cycle of HIV-1. The HIV-1 envelope glycoprotein gp120 plays an important role in initiating virus entry by targeting the primary cell receptor CD4. We explored the substitution of bulky molecular groups in region I in the NBD class of entry inhibitors. Previous attempts at bulky substituents in that region abolished antiviral activity, even though the binding site is hydrophobic. We synthesized a series of entry inhibitors containing the 1,3-benzodioxolyl moiety or its bioisostere, 2,1,3-benzothiadiazole. The introduction of the bulkier groups was well tolerated, and despite only minor improvements in antiviral activity, the selectivity index of these compounds improved significantly.
Keywords:
ENV-pseudovirus; HIV-1; antiviral agents; reverse transcriptase; structure-activity relationships.
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, N.I.H., Extramural
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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 / metabolism
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Anti-HIV Agents / pharmacology*
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Benzodioxoles / chemical synthesis
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Benzodioxoles / chemistry
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Benzodioxoles / metabolism
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Benzodioxoles / pharmacology*
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Binding Sites
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HIV Envelope Protein gp120 / chemistry
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HIV Envelope Protein gp120 / metabolism*
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HIV Reverse Transcriptase / antagonists & inhibitors
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HIV-1 / chemistry
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HIV-1 / enzymology
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Humans
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Leukocytes, Mononuclear / virology
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Molecular Docking Simulation
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Molecular Structure
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Protein Binding / drug effects
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / metabolism
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Pyrroles / pharmacology*
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry
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Reverse Transcriptase Inhibitors / metabolism
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Reverse Transcriptase Inhibitors / pharmacology
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry
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Thiadiazoles / metabolism
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Thiadiazoles / pharmacology
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Virus Internalization / drug effects*
Substances
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Anti-HIV Agents
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Benzodioxoles
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HIV Envelope Protein gp120
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Pyrroles
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Reverse Transcriptase Inhibitors
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Thiadiazoles
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase