Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazine hybrids incorporating an isoindole-1,3-dione scaffold as potent α-glucosidase inhibitors
Özet
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 1
H/ 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 KI values
ranging from 0.452 to 1.788 μM. Notably, the most active compound, TR6 (KI: 0.452 ± 0.093 μM), demonstrated
approximately 15-fold greater potency compared to the reference drug acarbose (KI: 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
Atıf için künye
Aslan, O. N., Kalın, Ş. N., Kalay, E., Türkeş, C., & Demir, Y. (2026). Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazine hybrids incorporating an isoindole-1,3-dione scaffold as potent α-glucosidase inhibitors. Bioorganic Chemistry, 1(1), 1–11. https://doi.org/10.1016/j.bioorg.2026.109767
BibTeX
@article{aslan2026-78793,
author = {Aslan, Osman Nuri and Kalın, Şeyda Nur and Kalay, Erbay and Türkeş, Cüneyt and Demir, Yeliz},
title = {Design, synthesis, in vitro and in silico evaluation of thiazole-hydrazine hybrids incorporating an isoindole-1,3-dione scaffold as potent α-glucosidase inhibitors},
journal = {Bioorganic Chemistry},
year = {2026},
volume = {1},
number = {1},
pages = {1--11},
issn = {0045-2068},
doi = {10.1016/j.bioorg.2026.109767},
url = {https://akademik.atauni.edu.tr/yayinlar/78793-design-synthesis-in-vitro-and-in-silico-evaluation-of-thiazole-hydrazine-hybrids}
}