1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents

Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These c...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2011-10, Vol.19 (19), p.5794-5802
Main Authors: Novikov, Mikhail S., Ivanova, Olga N., Ivanov, Alexander V., Ozerov, Alexander A., Valuev-Elliston, Vladimir T., Temburnikar, Kartik, Gurskaya, Galina V., Kochetkov, Sergey N., Pannecouque, Christophe, Balzarini, Jan, Seley-Radtke, Katherine L.
Format: Article
Language:English
Subjects:
Amino Acid Substitution
antiretroviral agents
Benzophenone
Benzophenones - chemistry
Cell Line
chemistry
drug resistance
Drug Resistance, Viral - drug effects
HIV Reverse Transcriptase - antagonists & inhibitors
HIV Reverse Transcriptase - genetics
HIV Reverse Transcriptase - metabolism
HIV-1
HIV-1 - drug effects
HIV-1 - enzymology
Human immunodeficiency virus
Human immunodeficiency virus 1
Humans
mutants
Non-nucleoside reverse transcriptase inhibitors
Reverse transcriptase
Reverse Transcriptase Inhibitors - chemical synthesis
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacology
RNA-directed DNA polymerase
Structure-Activity Relationship
therapeutics
Uracil
Uracil - analogs & derivatives
Uracil - chemical synthesis
Uracil - pharmacology
uracil derivatives
viruses
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Summary:Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing ω-(2-benzyl- and 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono- and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2011.08.025