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<p>A novel series of thiadiazole-linked thiazolidinone–chalcone derivatives was synthesized and comprehensively evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structural characterization was confirmed through <sup>1</sup>H-NMR, <sup>13</sup>C-NMR, and HREI-MS analyses. Among the synthesized compounds, analog 10 exhibited the most potent inhibitory activity with IC<sub>50</sub> values of 3.10 ± 0.20 µM (AChE) and 3.80 ± 0.20 µM (BChE), surpassing the standard drug donepezil (IC<sub>50</sub> = 5.50 ± 0.10 µM and 6.10 ± 0.20 µM, respectively). Other analogs demonstrated moderate to good activity within the range of 3.10–15.60 µM. In silico analyses, including molecular docking, pharmacophore modeling, molecular dynamics simulations, DFT calculations, and ADMET profiling, supported the experimental results and revealed stable binding conformations and favorable drug-like properties. The strong correlation between computational predictions and experimental data validated the proposed structure–activity relationship. These findings highlight compound 10 as a promising lead molecule for further optimization and development of effective and safe cholinesterase inhibitors for Alzheimer’s disease therapy.</p>

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From concept to simulations: computational and experimental assessment of thiadiazole–thiazolidinone hybrid chalcones for anti-alzheimer potentials

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Muhammad Bilal Khan,
  • Shoaib Khan,
  • Tayyiaba Iqbal,
  • Sampath Chinnam,
  • Eman Alzahrani,
  • Sobhi M. Gomha,
  • Magdi E. A. Zaki,
  • Kayumov Khasan Yusuf Ogli

摘要

A novel series of thiadiazole-linked thiazolidinone–chalcone derivatives was synthesized and comprehensively evaluated for their inhibitory potential against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Structural characterization was confirmed through 1H-NMR, 13C-NMR, and HREI-MS analyses. Among the synthesized compounds, analog 10 exhibited the most potent inhibitory activity with IC50 values of 3.10 ± 0.20 µM (AChE) and 3.80 ± 0.20 µM (BChE), surpassing the standard drug donepezil (IC50 = 5.50 ± 0.10 µM and 6.10 ± 0.20 µM, respectively). Other analogs demonstrated moderate to good activity within the range of 3.10–15.60 µM. In silico analyses, including molecular docking, pharmacophore modeling, molecular dynamics simulations, DFT calculations, and ADMET profiling, supported the experimental results and revealed stable binding conformations and favorable drug-like properties. The strong correlation between computational predictions and experimental data validated the proposed structure–activity relationship. These findings highlight compound 10 as a promising lead molecule for further optimization and development of effective and safe cholinesterase inhibitors for Alzheimer’s disease therapy.