Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazine hybrids incorporating an isoindole-1,3-dione scaffold as potent α-glucosidase inhibitors

In this study, a series of novel hybrid molecules ( TR1–14 ) incorporating a thiazole-hydrazine pharmacophore with a bicyclic isoindole-1,3-dione core were designed and synthesized. All compounds were unambiguously characterized by 1H/ 13C NMR, FTIR, and high-resolution mass spectrometry, and their purities (˃95%) were confirmed by HPLC. The synthesized derivatives exhibited potent α-glucosidase inhibition, with K I values ranging from 0.452 to 1.788 μM. Notably, the most active compound, TR6 ( K I: 0.452 ± 0.093 μM), demonstrated approximately 15-fold greater potency compared to the reference drug acarbose ( K I: 6.748 ± 0.167 μM), highlighting the substantial enhancement achieved through the designed scaffold modification. Structure–activity relationship analysis demonstrated that halogen substitution, particularly with chlorine and bromine, significantly enhances inhibitory potency, presumably due to strengthened hydrophobic and electronic interactions within the enzyme active site. Molecular docking and molecular dynamics simulations supported the experimental findings by revealing a conserved binding mode involving key catalytic residues (Arg600, Asp518, and Met519), as well as stabilizing water-mediated interactions, thereby providing a mechanistic rationale for the observed inhibition. In silico ADME predictions indicated favorable drug-like properties for all compounds, with full compliance with Lipinski's and Jorgensen's rules and substantially improved permeability profiles compared to acarbose. Cytotoxicity analyses demonstrated that TR3 , TR6 , TR10 , and TR11 exhibited low cytotoxic effects at concentrations above 100 μM in non-cancerous human lung epithelial BEAS-2B cells. Especially, TR5 and TR9 did not cause significant cytotoxicity even at a concentration of 200 μM in BEAS-2B cells. Overall, this integrated experimental-computational study identifies thiazole-hydrazine-isoindole hybrids, particularly TR5 and TR6 , as promising lead candidates for further optimization toward the development of next-generation α-glucosidase inhibitors with improved efficacy and drug-likeness. Copyright © 2024. Published by Elsevier Inc.