Thiazolidine Based Quinazoline Hybrids: Synthesis, Docking, DFT, Molecular Dynamic Study, and In Vitro Antidiabetic Evaluation

Abstract

Objective: This study aimed to design, synthesize, and evaluate thiazolidinedione and rhodanine-based quinazoline derivatives (Va–Vc) as dual inhibitors of α-amylase and α-glucosidase, with an investigation into their pharmacokinetic properties and mechanism of action using a computational approach. Methods: The compounds were designed computationally and synthesized using appropriate synthons. In silico molecular docking and molecular dynamics simulations were employed to explore their interactions with α-amylase, GLUT-4, and homology-modeled α-glucosidase. Pharmacokinetic properties, including drug-likeness, ADME, and toxicity, were predicted. Network pharmacology and experimental validation were used to assess the modulation of PI3K-AKT, MAPK, and EGFR signaling pathways, as well as inhibitory activities against α-amylase, α-glucosidase, and glucose uptake by yeast cells. Results and Discussion: The derivatives exhibited promising inhibitory activities. Substituted benzylidine thiazolidine-2,4-dione showed IC₅₀ values of 22.59 ± 0.30 µM for α-amylase and 43.50 ± 1.23 µM for α-glucosidase, with 58.23 ± 0.14% glucose uptake. Substituted benzylidene-4-oxo-2-thioxothiazolidin-3-yl acetic acid displayed IC₅₀ values of 13.48 ± 1.38 µM for α-amylase and 65.94 ± 0.14 µM for α-glucosidase, with 57.23 ± 0.13% glucose uptake. These compounds modulated key signaling pathways, contributing to their inhibitory effects and favorable pharmacokinetic profiles. Conclusions: The study highlights the potential of thiazolidinedione and rhodanine-based quinazoline derivatives as novel α-amylase and α-glucosidase inhibitors, offering promising therapeutic potential for managing diabetes mellitus.