Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 26, Issue 11, Pages 2706-2712Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2016.04.002
Keywords
Phosphatidylinositol 4-kinase; Purine; PI4K III beta; Antiviral agent; Hepatitis C virus
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Funding
- Czech Science Foundation
- Academy of Sciences of the Czech Republic [RVO: 61388963]
- Project NPU I from the Ministry of Education, Youth and Sports [LO 1302]
- Gilead Sciences Inc.
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We report on an extensive structure-activity relationship study of novel PI4K III beta 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 III beta 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. (C) 2016 Published by Elsevier Ltd.
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