新型苯并硫氮杂 酮类非ATP竞争GSK-3β抑制剂的设计、合成和活性评价

Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. Most of known inhibitors are bound in the ATP-binding pocket of GSK-3, which might lead widespread effects. Non-ATP-competitive GSK-3 inhibitors actually represent a more efficient pathway for providing real promising drugs for therapeutic intervention. As an initial step of our work to discover such non-ATP-competitive GSK-3 inhibitors, a virtual screening was conducted by Autodock program, which docked the small drug-like molecules of Maybridge library at the non-ATP-binding site of GSK-3β. 2, 3-Dihydrobenzo[b][1, 4] thiazepine-4(5H)-ones (1) with variable substitutes ranked in the top of hits, likely potentially having inhibition and highly selectivity to GSK-3β. Eight derivatives of (1) had been designed based on the virtual screening result and successfully synthesized through Knoevenagel reaction, cyclization and N-alkylation. Among them, 5-benzyl-2-(furan-2-yl)-2, 3-dihydrobenzo[b][1, 4] thiazepin -4(5H)-one (4c) showed moderate inhibition to GSK-3β in vitro (IC50 = 47.69 ± 2.38µM) tested by the National Center for Drug Screening of China. The discovered new active compound (4c) is structurally different to other inhibitors of GSK-3β and worthy of further study as a novel lead compound.