Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design

Abstract

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential alpha-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 +/- 0.02 mu M, similar to 2183-fold higher than acarbose having an IC50 of 873.34 +/- 1.67 mu M. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of alpha-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of alpha-glucosidase.