•Novel benzothiazinones were synthesized and proved to be potent and selective GSK 3β inhibitors.•The mechanism of inhibition to GSK 3β was proved to be non-ATP competitive.•Most of these inhibitors showed good antitumor activity against ovarian cancer cell lines.•Compound 20g could arrest G0/G1 cell cycle and induce apoptosis of A2780 cells.•Compound 20g also exhibited moderate antitumor activity in a female BALB/C nude mice model.Glycogen synthase kinase 3β (GSK 3β) is a highly conserved serine/threonine kinase, and its roles in cancer remain controversial. Cumulative evidence supported that GSK 3β inhibitors could suppress ovarian cancer (OC) development in vitro and made a new direction for ovarian cancer treatment. Here, we reported a series of novel substituted benzothiazinones as non-ATP competitive inhibitors of GSK 3β. Further studies showed that most of them had antiproliferative activities in ovarian cancer cell lines in vitro. As the most promising candidate of them, compound 20g induced cells apoptosis, arrested the cell cycle at the G1 phase in the A2780 cell line and showed moderate suppression efficacy in a female BALB/C nude mice model. All of the results demonstrated that compound 20g, as the first reported non-ATP competitive small molecule inhibitor of GSK 3β with suppression efficacy on ovarian cancer both in vitro and in vivo, might represent a potential candidate for the treatment of OC.Download high-res image (134KB)Download full-size image

•An efficient method for the construction of 1,5-benzothiozepinone framework.•TBAF catalyzes Michael addition and intramolecular amidation in mild condition.•Moderate electron -donating/-withdrawing groups smoothly undergo the cyclization.•A environmentally friendly reaction due to its solvent-free condition.A practical and efficient method for the preparation of 1,5-benzothiazepinone derivatives in good yields has been developed using tetrabutylammonium fluoride (TBAF) as a catalyst. This study not only expands the previous work on the substrate scope and also provides more understanding of the chemistry of such drug scaffolds.

Glycogen synthase kinase-3β (GSK-3β) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3β have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 6l, 6t and 6v have the IC50 values of 25.0 μM, 27.8 μM and 23.0 μM, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.Graphical abstract2,3-dihydro-2,5-disubstituted-1,5-benzothiazepin-4(5H)-one.Highlights► A series of 2,3-dihydro-2,5-disubstituted-1,5-benzothiazepin-4(5H)-one were synthesized. ► These compounds showed GSK-3β inhibitory activities in vitro. ► Kinetic analysis showed compound 6v is non-ATP GSK-3β inhibitor. ► Molecular docking studies suggested the putative binding modes.

Glycogen synthase kinase-3β (GSK-3β) is an important serine/threonine kinase that has been proved as a key target for neurodegenerative diseases and diabetes. Up to date, most of known inhibitors are bound to the ATP-binding pocket of GSK-3β, which might lead widespread effects due to the high homology between kinases. Recently, some of its non-ATP competitive inhibitors had been confirmed having therapeutical effects owing to their high selectivity. This finding opens a new pathway to study hopeful drugs for treatment of these diseases. However, it is still a challenge nowadays on how to efficiently find non-ATP competitors. Here, we successfully discovered a novel scaffold of benzothiazepinones (BTZs) as selective non-ATP competitive GSK-3β inhibitors through virtual screening approach. A 3D receptor model of substrate binding site of GSK-3β was constructed and applied to screen against drug-like Maybridge database through Autodock program. BTZ compounds were top ranked as efficient hits and were then synthesized for further screening. Among them, the representative compound 4j showed activity to GSK-3β (IC50: 25 μM) in non-ATP competitive mechanism, and nearly no inhibitory effect on other 10 related protein kinases. Overall, the results point out that BTZ compounds might be useful in treatment of Alzheimer’s disease and diabetes mellitus as novel GSK-3β inhibitors. It also suggests, on the other hand, that virtual screening would provide a valuable tool in combination with in vitro assays for the identification of novel selective and potent inhibitors.

HIV-1 integrase is an essential enzyme for viral replication and a validated target for the development of drugs against AIDS. With an aim to discover new potent inhibitors of HIV-1 integrase, we developed a pharmacophore model based on reported inhibitors embodying structural diversity. Eight compounds of 2-pyrrolinones fitting all the features of the pharmacophore query were found through the screening of an in-house database. These candidates were successfully synthesized, and three of them showed strand transfer inhibitory activity, in which, one compound showed antiviral activity. Further mapping analysis and docking studies affirmed these results.A pharmacophore model based on reported HIV-1 integrase inhibitors was developed. Eight compounds of 2-pyrrolinones fitting all the features of the pharmacophore query were found through the screening of an in-house database and were synthesized, three of them showed strand transfer inhibitory activity and one of them showed antiviral activity.