Exploring efficacy of natural-derived acetylphenol scaffold inhibitors for α-glucosidase: Synthesis, in vitro and in vivo biochemical studies.

The discovery of novel α-glucosidase inhibitors and anti-diabetic candidates from natural or natural-derived products represents an attractive therapeutic option. Here, a collection of acetylphenol analogues derived from paeonol and acetophenone were synthesized and evaluated for their α-glucosidase inhibitory activity. Most of derivatives, such as 9a-9e, 9i, 9m-9n and 11d-1e, (IC = 0.57 ± 0.01 μM to 8.45 ± 0.57 μM), exhibited higher inhibitory activity than the parent natural products and were by far more potent than the antidiabetic drug acarbose (IC = 57.01 ± 0.03 μM). Among these, 9e and 11d showed the most potent activity in a non-competitive manner. The binding processes between the two most potent compounds and α-glucosidase were spontaneous. Hydrophobic interactions were the main forces for the formation and stabilization of the enzyme - acetylphenol scaffold inhibitor complex, and induced the topography image changes and aggregation of α-glucosidase. In addition, everted intestinal sleeves in vitro and the maltose loading test in vivo further demonstrated the α-glucosidase inhibition of the two compounds, and our findings proved that they have significant postprandial hypoglycemic effects.