Abstract
Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that incorporate a 7-indolizinylamino or 2-naphthylamino substituent on a pyrimidine or 1,3,5-triazine core. The most potent compounds show below 10 nanomolar activity towards wild-type HIV-1 and variants bearing Tyr181Cys and Lys103Asn/Tyr181Cys resistance mutations. The compounds also feature good aqueous solubility. Crystal structures for two complexes enhance the analysis of the structure-activity data.
Keywords:
Drug solubility; HIV-1 reverse transcriptase; NNRTI; Protein crystallography; Structure-based drug design.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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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Azabicyclo Compounds / chemical synthesis
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Azabicyclo Compounds / chemistry
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Azabicyclo Compounds / pharmacology*
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Bridged Bicyclo Compounds / chemical synthesis
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Bridged Bicyclo Compounds / chemistry
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Bridged Bicyclo Compounds / pharmacology*
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Cell Line
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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HIV / drug effects*
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / metabolism
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Humans
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Models, Molecular
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Molecular Structure
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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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Solubility
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Structure-Activity Relationship
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Triazines / chemical synthesis
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Triazines / chemistry
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Triazines / pharmacology*
Substances
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Anti-HIV Agents
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Azabicyclo Compounds
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Bridged Bicyclo Compounds
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Reverse Transcriptase Inhibitors
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Triazines
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HIV Reverse Transcriptase