Anti-Inflammatory Effect of Novel 7-Substituted Coumarin Derivatives through Inhibition of NF-κB Signaling Pathway.

A series of novel 7-substituted coumarin derivatives were synthesized and evaluated. Biological screening results obtained by the evaluation of the compounds' inhibition against LPS-induced IL-6 and TNF-α release in RAW 264.7 cells indicated that most compounds exhibited potent anti-inflammatory activity. Among them, N-(3-methoxybenzyl)-2-[(2-oxo-2H-chromen-7-yl)oxy]acetamide (2d) showed the best activity. The potential targets of title compound 2d were reversely screened with the molecular modeling software, Discovery Studio 2017 R2. Screening and molecule docking results showed that 2d could bind to the active site (NLS Polypeptide) of NF-κB p65, and this binding affinity was confirmed by surface plasmon resonance (SPR) analysis. Furthermore, Western blot assay showed that 2d remarkably blocked the NF-κB signaling pathway in vitro. Collectively, all these findings suggested that compound 2d might be a promising lead compound worthy of further pursuit.

Imazamethabenz inhibits human breast cancer cell proliferation, migration and invasion via combination with Pin1.

Overexpression of peptidyl-prolyl cis/trans isomerase, NIMA interacting­1 (Pin1) is a significant marker of the occurrence and development of tumors. In the present study, the imidazoline ketone herbicide imazamethabenz was investigated as a potential antitumor drug by inhibiting Pin1. Molecular docking and enzyme activity tests verified, for the first time, that the imidazoline ketone compound imazamethabenz effectively inhibited Pin1 in vitro. MTT assays, western blotting, wound healing assay and Matrigel invasion assays revealed that imazamethabenz induced apoptosis and inhibited migration and invasion of the breast cancer cell line MCF­7, which overexpresses Pin1, by inhibiting the Pin1­mediated signaling pathway involving vascular endothelial growth factor and matrix metalloproteinase 9. These findings indicated that imazamethabenz offers potential applications for the treatment of tumors as a Pin1 inhibitor.

Graveoline Analogs Exhibiting Selective Acetylcholinesterase Inhibitory Activity as Potential Lead Compounds for the Treatment of Alzheimer's Disease.

This study designed and synthesized a series of new graveoline analogs on the basis of the structural characteristics of acetylcholinesterase (AChE) dual-site inhibitors. The activity of these analogs was also evaluated. Results showed that the synthesized graveoline analogs displayed stronger inhibitory activity against AChE and higher selectivity than butyrylcholine esterase (BuChE) (Selectivity Index from 45 to 486). When the two sites in the graveoline parent ring substituting phenyl and amino terminal had six chemical bonds (n = 3) and the terminal amino was piperidine, compound 5c showed the best activity. Furthermore, the mechanism of action and binding mode were explored by enzyme kinetic simulation, molecular docking, and thioflavin T-based fluorometric assay. Cytotoxicity assay showed that the low concentration of the analogs did not affect the viability of the neurocyte SH-SY5Y.