Combining symmetry elements results in potent naphthyridinone (NTD) HIV-1 integrase inhibitors

A series of naphthyridinone HIV-1 integrase strand-transfer inhibitors have been designed based on a psdeudo-C2 symmetry element present in the two-metal chelation pharmacophore. A combination of two distinct inhibitor binding modes resulted in potent inhibition of the integrase strand-transfer reac...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6461-6464
Main Authors: Johns, Brian A., Kawasuji, Takashi, Weatherhead, Jason G., Boros, Eric E., Thompson, James B., Garvey, Edward P., Foster, Scott A., Jeffrey, Jerry L., Miller, Wayne H., Kurose, Noriyuki, Matsumura, Kenichi, Fujiwara, Tamio
Format: Article
Language:English
Subjects:
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral
Antiviral agents
antiviral properties
Biological and medical sciences
chelation
HAART
HIV Integrase
HIV Integrase Inhibitors - pharmacology
HIV-1
Human immunodeficiency virus 1
Medical sciences
Naphthyridines - chemistry
Naphthyridines - pharmacology
Naphthyridinone
pharmacology
Pharmacology. Drug treatments
protein binding
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Summary:A series of naphthyridinone HIV-1 integrase strand-transfer inhibitors have been designed based on a psdeudo-C2 symmetry element present in the two-metal chelation pharmacophore. A combination of two distinct inhibitor binding modes resulted in potent inhibition of the integrase strand-transfer reaction in the low nM range. Effects of aryl and N1 substitutions are disclosed including the impact on protein binding adjusted antiviral activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.08.082