Abstract
A series of novel 4,6-diarylpyrimidines (4,6-DAPY) and diarylbenzenes (DABE) compounds were synthesized and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Among them, the most potent HIV-1 inhibitors were 8b, 8d, 14b and 18 (EC(50) = 0.049, 0.381, 0.599 and 0.398 μM, respectively), with HIV-1 inhibitory activity improved or similar to nevirapine (NVP, EC(50) = 0.097 μM) and delavirdine (DEV, EC(50) = 0.55 μM). The other compounds displayed moderate activity (8c, EC(50) = 5.25 μM) or were inactive (8a and 14a) against HIV-1 replication. Molecular modeling studies were performed with the synthesized compounds in complex with the wild-type reverse transcriptase (RT). A correlation was found between the anti-HIV activity and the electrostatic energy of interaction with Lys101 residue. These findings enrich the SAR of these Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) families.
Copyright © 2012 Elsevier Masson SAS. 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 / chemistry
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Anti-HIV Agents / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzene Derivatives / chemical synthesis
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Benzene Derivatives / chemistry
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Benzene Derivatives / pharmacology*
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Cell Survival / drug effects
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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HIV Reverse Transcriptase / antagonists & inhibitors*
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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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HIV-1 / genetics
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HIV-2 / drug effects
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HIV-2 / enzymology
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HIV-2 / genetics
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Humans
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Models, Molecular
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Molecular Structure
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / 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 / pharmacology*
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Structure-Activity Relationship
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Tumor Cells, Cultured
Substances
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Anti-HIV Agents
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Antineoplastic Agents
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Benzene Derivatives
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Pyrimidines
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Reverse Transcriptase Inhibitors
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HIV Reverse Transcriptase