Pyrano[2,3-b]chromone derivatives as novel dual inhibitors of α-glucosidase and α-amylase: Design, synthesis, biological evaluation, and in silico studies

Abstract

Inhibition of alpha-glucosidase and alpha-amylase is an important target for treatment of type 2 diabetes. In this work, a novel series of pyrano[2,3-b]chromene derivatives 5a -m was designed based on potent alpha-glucosidase and alpha-amylase inhibitors and synthesized by simple chemical reactions. These compounds were evaluated against the latter enzymes. Most of the title compounds exhibited high inhibitory activity against alpha-glucosidase and alpha-amylase in comparison to standard inhibitor (acarbose). Representatively, the most potent compound, 4methoxy derivative 5d, was 30.4 fold more potent than acarbose against alpha-glucosidase and 6.1 fold more potent than this drug against alpha-amylase. In silico molecular modeling demonstrated that compound 5d attached to the active sites of alpha-glucosidase and alpha-amylase with a favorable binding energies and established interactions with important amino acids. Dynamics of compound 5d also showed that this compound formed a stable complex with the alpha-glucosidase active site. In silico drug-likeness as well as ADMET prediction of this compound was also performed and satisfactory results were obtained.