Eastern extension of azoles as non-nucleoside inhibitors of HIV-1 reverse transcriptase; cyano group alternatives

Synthesis, assaying, and computational results are reported for new anti-HIV agents that exhibit high potency and low cytotoxicity. Extension into an eastern channel in the HIV-1 reverse transcriptase binding site is investigated. Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (8), p.2485-2488
Main Authors: Leung, Cheryl S., Zeevaart, Jacob G., Domaoal, Robert A., Bollini, Mariela, Thakur, Vinay V., Spasov, Krasimir A., Anderson, Karen S., Jorgensen, William L.
Format: Article
Language:English
Subjects:
Anti-HIV drugs
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Azoles - chemistry
Azoles - pharmacology
Biological and medical sciences
Free-energy calculations
HIV-1 - enzymology
Human immunodeficiency virus 1
Medical sciences
Models, Molecular
NNRTIs
Pharmacology. Drug treatments
Reverse Transcriptase Inhibitors - chemistry
Reverse Transcriptase Inhibitors - pharmacology
Structure-based design
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Summary:Synthesis, assaying, and computational results are reported for new anti-HIV agents that exhibit high potency and low cytotoxicity. Extension into an eastern channel in the HIV-1 reverse transcriptase binding site is investigated. Design of non-nucleoside inhibitors of HIV-1 reverse transcriptase is being pursued with the assistance of free energy perturbation (FEP) calculations to predict relative free energies of binding. Extension of azole-containing inhibitors into an ‘eastern’ channel between Phe227 and Pro236 has led to the discovery of potent and structurally novel derivatives.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.03.006