Purine analogs as phosphatidylinositol 4-kinase IIIβ inhibitors
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27090557
PubMed Central
PMC7127540
DOI
10.1016/j.bmcl.2016.04.002
PII: S0960-894X(16)30363-8
Knihovny.cz E-resources
- Keywords
- Antiviral agent, Hepatitis C virus, PI4K IIIβ, Phosphatidylinositol 4-kinase, Purine,
- MeSH
- Antiviral Agents chemical synthesis chemistry pharmacology MeSH
- Enterovirus B, Human drug effects MeSH
- Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors metabolism MeSH
- HeLa Cells MeSH
- Hepacivirus drug effects MeSH
- Protein Kinase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Purines chemical synthesis chemistry pharmacology MeSH
- Rhinovirus drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antiviral Agents MeSH
- Phosphotransferases (Alcohol Group Acceptor) MeSH
- Protein Kinase Inhibitors MeSH
- phosphatidylinositol 4-kinase IIIbeta, human MeSH Browser
- purine MeSH Browser
- Purines MeSH
We report on an extensive structure-activity relationship study of novel PI4K IIIβ inhibitors. The purine derivative of the potent screening hit T-00127-HEV1 has served as a suitable starting point for a thorough investigation of positions 8 and 2. While position 8 of the purine scaffold can only bear a small substituent to maintain the inhibitory activity, position 2 is opened for extensive modification and can accommodate even substituted phenyl rings without the loss of PI4K IIIβ inhibitory activity. These empirical observations nicely correlate with the results of our docking study, which suggests that position 2 directs towards solution and can provide the necessary space for the interaction with remote residues of the enzyme, whereas the cavity around position 8 is strictly limited. The obtained compounds have also been subjected to antiviral screening against a panel of (+)ssRNA viruses.
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