Identification, Design and Computational Insights of Hybrid Thiadiazole Linked Fused Thiazole-Isoxazole as Potent Dual Inhibitor of AChE/BChE Alzheimer's Disease
In vitro and in silico study demonstrates dual cholinesterase inhibition by hybrid thiadiazole derivatives, suggesting potential for targeted Alzheimer's disease therapeutics.
Key Points
To design, synthesize, and evaluate a novel series of hybrid thiadiazole-linked fused thiazole-isoxazole derivatives as potential dual AChE and BuChE inhibitors for Alzheimer's disease.
Synthesized a library of 12 novel hybrid derivatives (1–12) and characterized them using 1H-NMR, 13C-NMR, FTIR, and HRMS spectroscopy.
Performed in vitro enzyme inhibition assays against AChE and BuChE with donepezil as the reference standard.
Conducted molecular docking, ADMET profiling, and density functional theory (DFT) calculations to assess binding modes and electronic properties.
Synthesized derivatives demonstrated dual inhibition with IC50 values ranging from 8.42 ± 0.34 to 28.78 ± 0.91 μM for AChE and 9.17 ± 0.60 to 28.16 ± 0.98 μM for BuChE, relative to donepezil (IC50 = 18.23 ± 0.93 μM for AChE; 20.38 ± 0.81 μM for BuChE).
Compounds 6, 5, 3, and 10 exhibited superior dual potency, with compound 6 achieving the lowest IC50 of 8.42 ± 0.34 μM for AChE and 9.17 ± 0.60 μM for BuChE.
SAR analysis and docking simulations revealed that electron-withdrawing and electron-donating substituents enhanced potency through favorable hydrogen bonding and π-π stacking inside the catalytic gorge.