# Rational design of phenyl 2,4,5-trichlorobenzenesulfonate based thiosemicarbazones as α-glucosidase and α-amylase inhibitors: integrating enzymatic evaluation and molecular modeling

## TL;DR

Researchers designed and tested new thiosemicarbazone compounds that effectively inhibit enzymes linked to diabetes, showing strong potential for drug development.

## Contribution

A new thiosemicarbazone derivative (compound 16) was identified as a potent dual inhibitor of α-glucosidase and α-amylase.

## Key findings

- Compound 16 showed IC50 values of 14.58 nM for α-glucosidase and 88.37 nM for α-amylase.
- Molecular docking and simulations confirmed stable interactions and conformational stability of compound 16 with enzyme active sites.
- ADME profiling predicted favorable pharmacokinetic properties for compound 16.

## Abstract

The present study aimed to investigate the antidiabetic potential of a new series of thiosemicarbazone derivatives through integrated in vitro enzymatic assays and in silico molecular modeling. The synthesized compounds were evaluated for their inhibitory activities against α-glucosidase (α-Glu) and α-amylase (α-Amy) enzymes. Among the tested derivatives, compound 16 (2-chlorophenyl-substituted) demonstrated the most potent dual inhibition with IC50 values of 14.58 nM (α-Glu) and 88.37 nM (α-Amy), surpassing the reference drug acarbose in potency. Molecular docking analyses revealed that compound 16 formed stable interactions with Asn-214, Glu-276, Phe-157, and Tyr-71 in the α-Glu and Asp-197, Glu-233, and Lys-200 in α-Amy's active site. These key interactions were further supported by 250 ns molecular dynamics simulations, confirming the conformational stability of both complexes with average RMSD values below 2.0 Å and minimal ligand fluctuations. Energy decomposition analysis indicated that van der Waals and electrostatic interactions were the major contributors to the overall binding free energy. In silico ADME profiling predicted favorable pharmacokinetic properties, including high gastrointestinal absorption, good oral bioavailability, and compliance with Lipinski's rule of five, while no significant blood–brain barrier penetration was observed. The combined in vitro and in silico findings highlight compound 16 as a promising lead candidate for further optimization and development as a dual α-Glu and α-Amy inhibitor for the management of type 2 diabetes mellitus.

A new series of thiosemicarbazone derivatives were synthesized and evaluated as dual α-Glu/α-Amy inhibitors.