Synthesis and Activity Evaluation of Novel Benzoxazepinone Derivatives as Potential Inhibitors of Glycogen Phosphorylase

TL;DR

This paper introduces new benzoxazepinone compounds that strongly inhibit glycogen phosphorylase, a key enzyme in glycogen breakdown.

Contribution

The study presents novel benzoxazepinone derivatives with potent glycogen phosphorylase inhibition and identifies compound 8g as a highly effective inhibitor.

Findings

Compound 8g inhibited rabbit muscle glycogen phosphorylase a with an IC50 of 0.62 ± 0.16 μM.

Compound 8g showed three times greater inhibition of glycogen degradation in HL-7702 cells compared to PSN-357.

Molecular docking suggests compound 8g forms stable hydrogen bonds and hydrophobic interactions with PYGL.

Abstract

Glycogen phosphorylase (GP) is a key enzyme of glycogen catabolism, so it is significant to discover a new GP inhibitor. A series of benzoxazepinone derivatives were identified as glycogen phosphorylase (GP) inhibitors with potent activity. These compounds exhibited strong inhibitory effects. Among them, compound 8g (IC50 = 0.62 ± 0.16 μM) showed significant inhibitory activity against rabbit muscle glycogen phosphorylase a (GPa). Its inhibition of glycogen degradation in HL-7702 cells was three times greater than that of PSN-357. Molecular docking studies revealed that the binding conformation of compound 8g with PYGL allowed the benzoxazinone moiety to form stable hydrogen-bond networks and hydrophobic interactions, which may explain its excellent activity.

Figures