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.

• 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