Screening bifunctional flavonoids of anti-cholinesterase and anti-glucosidase by in vitro and in silico studies: Quercetin, kaempferol and myricetin

Type 2 diabetes mellitus (T2DM) and Alzheimer disease (AD) are two independent non-infectious diseases, however, evidences demonstrate that insulin resistance (IR) directly affects the glucose metabolism of the central nervous system (CNS), ultimately leading to neurodegenerative disorders, such as AD. Therefore, developing anti-AD/-diabetes inhibitors with fewer side effects have become a focus of the public and pharmacologist. In this study, the inhibitory activities of 16 flavonoids and 3 standards (galantamine, donepezil hydrochloride and acarbose) on acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-glucosidase (αG) and α-amylase (αA) and their corresponding structure-activity relationships were studied by multiple methods. The results showed that, unlike the positive effect of hydroxyl group, methoxy group of flavonoids had a negative effect on the inhibitory activity of enzyme. Besides, the glycosylation of C3 and C7 significantly reduced the inhibitory effect of flavonoids, and the hydrogenation of C2 = C3 double bond also had a similar inhibitory effect. Hence, flavonols, especially quercetin, kaempferol and myricetin showed high anti-AChE/-BChE/-αG/-αA activities, and their activities had a highest correlation with their antioxidant activities, while catechin, epicatechin, and artemetin had low inhibitory activities. Furthermore, molecular docking further confirmed the C4′-OH, C5′-OH and C3–OH of flavonoids skeleton played an important role in the binding and interaction between flavonoids and enzymes. In conclusion, flavonoids with specific structures may be used as inhibitors of cholinesterase, αG and αA in the treatment and prevention of AD and T2DM.