Purine analogs as phosphatidylinositol 4-kinase III beta inhibitors

0460249 - ÚOCHB 2017 RIV GB eng J - Journal Article
Šála, Michal - Kögler, Martin - Plačková, Pavla - Mejdrová, Ivana - Hřebabecký, Hubert - Procházková, Eliška - Strunin, Dmytro - Lee, G. - Birkuš, G. - Weber, Jan - Mertlíková-Kaiserová, Helena - Nencka, Radim
Purine analogs as phosphatidylinositol 4-kinase III beta inhibitors.
Bioorganic and Medicinal Chemistry Letters. Roč. 26, č. 11 (2016), s. 2706-2712. ISSN 0960-894X. E-ISSN 1464-3405
R&D Projects: GA ČR GA15-09310S; GA MŠMT LO1302
Institutional support: RVO:61388963
Keywords : phosphatidylinositol 4-kinase * purine * PI4K III beta * antiviral agent * hepatitis C virus
Subject RIV: CC - Organic Chemistry
Impact factor: 2.454, year: 2016

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.
Permanent Link: http://hdl.handle.net/11104/0260372