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<p>Neurodegenerative disorders such as Parkinson’s disease are closely associated with dysregulated activity of monoamine oxidase-B (MAO-B), which leads to dopamine depletion and oxidative stress. Despite the availability of numerous monoamine oxidase (MAO) inhibitors on the market, their irreversibility and associated side effects necessitate the development of more effective and reversible MAO-B inhibitors. In this study, a series of twenty-one indole-based derivatives <b>(PSH1</b>-<b>PSH21)</b>, collectively designated as <b>PSH</b>, was synthesised and evaluated for inhibitory activity against MAO isoforms. Most synthesised compounds showed higher inhibitory activity toward MAO-B than MAO-A, indicating selectivity for MAO-B. Among the <b>PSH</b> derivatives, <b>PSH18</b> exhibited the most potent MAO-B inhibitory activity (IC<sub>50</sub> = 0.95 ± 0.02 µM), followed by <b>PSH6 (</b>IC<sub>50</sub> = 1.79 ± 0.40 µM) and <b>PSH2</b> (IC<sub>50</sub> = 1.96 ± 0.08 µM). Compound <b>PSH18</b> showed the highest selectivity index value of 42.11, followed by <b>PSH6</b> (22.35) and <b>PSH2</b> (20.41). Additionally, <b>PSH18</b> was confirmed to be a competitive and reversible inhibitor of MAO-B with an inhibition constant value of 0.89 ± 0.035 µM. Notably, <b>PSH18</b> exhibited good permeability across the blood–brain barrier in parallel artificial membrane permeability assay experiments, along with acceptable absorption, distribution, metabolism, excretion, and toxicity parameters predicted through in silico modelling, suggesting its potential as a central nervous system-targeted molecule. Molecular docking and a 200 ns molecular dynamics simulation demonstrated stable binding of the ligand to the MAO-B active-site pocket, driven by hydrophobic and π–π stacking interactions with key amino acid residues lining the aromatic cage. Moreover, the calculated binding energy indicated strong ligand–protein interactions. Overall, these results indicate that the <b>PSH</b> scaffold could serve as a promising lead structure for the development of potent and selective MAO-B inhibitors. These compounds may have therapeutic potential for the treatment of neurodegenerative diseases.</p>

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Synthesis, biological evaluation and in silico studies of novel propargyl-tethered isatin hydrazones as monoamine oxidase inhibitors for Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Saranya Kattil Parmbil,
  • Hee Jung Kim,
  • Jaeyeop Lim,
  • Mohamed A. Abdelgawad,
  • Mohamed Sadek Abdel-Bakky,
  • Mohammed M. Ghoneim,
  • Harish Chandra Vishwakarma,
  • Sunil Kumar,
  • Sandeep Kumar,
  • Hoon Kim,
  • Bijo Mathew

摘要

Neurodegenerative disorders such as Parkinson’s disease are closely associated with dysregulated activity of monoamine oxidase-B (MAO-B), which leads to dopamine depletion and oxidative stress. Despite the availability of numerous monoamine oxidase (MAO) inhibitors on the market, their irreversibility and associated side effects necessitate the development of more effective and reversible MAO-B inhibitors. In this study, a series of twenty-one indole-based derivatives (PSH1-PSH21), collectively designated as PSH, was synthesised and evaluated for inhibitory activity against MAO isoforms. Most synthesised compounds showed higher inhibitory activity toward MAO-B than MAO-A, indicating selectivity for MAO-B. Among the PSH derivatives, PSH18 exhibited the most potent MAO-B inhibitory activity (IC50 = 0.95 ± 0.02 µM), followed by PSH6 (IC50 = 1.79 ± 0.40 µM) and PSH2 (IC50 = 1.96 ± 0.08 µM). Compound PSH18 showed the highest selectivity index value of 42.11, followed by PSH6 (22.35) and PSH2 (20.41). Additionally, PSH18 was confirmed to be a competitive and reversible inhibitor of MAO-B with an inhibition constant value of 0.89 ± 0.035 µM. Notably, PSH18 exhibited good permeability across the blood–brain barrier in parallel artificial membrane permeability assay experiments, along with acceptable absorption, distribution, metabolism, excretion, and toxicity parameters predicted through in silico modelling, suggesting its potential as a central nervous system-targeted molecule. Molecular docking and a 200 ns molecular dynamics simulation demonstrated stable binding of the ligand to the MAO-B active-site pocket, driven by hydrophobic and π–π stacking interactions with key amino acid residues lining the aromatic cage. Moreover, the calculated binding energy indicated strong ligand–protein interactions. Overall, these results indicate that the PSH scaffold could serve as a promising lead structure for the development of potent and selective MAO-B inhibitors. These compounds may have therapeutic potential for the treatment of neurodegenerative diseases.