Flavonoids as alpha-glucosidase inhibitors: mechanistic approaches merged with enzyme kinetics and molecular modelling

Diabetes mellitus is a major, global public health problem. alpha-Glucosidase inhibitors are one of the most widely used classes of oral antidiabetics. In addition to other pharmaceutical benefits, flavonoids are known as potent alpha-glucosidase inhibitors. In the last two decades, the latter property of flavonoids has attracted a great interest. In the current review, the literature on flavonoids as inhibitors of alpha-glucosidase enzyme, their mechanism of action along with in silico studies and structure-activity relationships is discussed. The main outcomes show that a double bond between C-2 and C-3, and free hydroxyl groups at C-3 and C-4 ' are crucial. Whereas sugar substitution at any position on the aglycon reduced the inhibitory effect, a phenolic group like gallic acid, coumaric acid, etc. substituted at different positions of sugar units increased it. Hydroxylation of flavonoids generally enhanced the effect due to possible electrostatic interactions with the enzyme, making flavonols stronger inhibitors than their flavone analogues. Hydroxyl groups at C-3, C-7, ring B, and the carbonyl oxygen at C-4 are considered to be key modifications to enhance binding through hydrogen bonds. With this overview we intend to motivate and challenge researchers to design novel flavonoids a find new hits.