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<p>Alzheimer’s disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer’s disease. The three synthesized compounds (<b>B1–B3</b>) were obtained in good yields (68–73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026&#xa0;eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80&#xa0;kcal/mol. Molecular docking results (kcal/mol) showed that <b>B1</b> (–7.09/–6.59), <b>B2</b> (–5.30/–6.78), and <b>B3</b> (–7.42/–6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (–6.66/–5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, <b>B1-B3</b> outperformed Rivastigmine against BChE with <b>B3</b> showing the strongest binding affinity (ΔG<sub>bind</sub> = − 28.10&#xa0;kcal/mol for AChE and − 26.31&#xa0;kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE–<b>B2</b> (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE–<b>B2</b> (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies <b>B1</b> - <b>B3</b> as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer’s disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles.</p>

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Targeting Alzheimer’s diseases via nitro-substituted Schiff base derivatives: synthesis, DFT, and molecular dynamics studies

  • 期刊论文

  • 发表日期：

    2026年1月14日

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  • Abosede A. Badeji,
  • Samuel O. Olalekan,
  • Adesola A. Adeleke,
  • Moses M. Edim,
  • Temiloluwa O. Olaniyi,
  • Omoyele O. Alli,
  • Okiki N. Quadri,
  • Segun D. Oladipo

摘要

Alzheimer’s disease, a major neurodegenerative disorder, is strongly linked to cholinergic dysfunction, making cholinesterase inhibition a key therapeutic strategy. Herein, the synthesis and in-silico studies of nitro-substituted Schiff base derivatives were studied as potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) targeting Alzheimer’s disease. The three synthesized compounds (B1–B3) were obtained in good yields (68–73%). DFT results showed that the vibrational frequencies agreed with the experimental data, and B3 had the smallest HOMO-LUMO gap (6.026 eV) from frontier molecular orbital analysis, indicating higher chemical reactivity. NBO analysis showed it exhibits a strong donor-acceptor interaction with a stabilization energy of 34.80 kcal/mol. Molecular docking results (kcal/mol) showed that B1 (–7.09/–6.59), B2 (–5.30/–6.78), and B3 (–7.42/–6.35) exhibited stronger interactions with AChE and BChE respectively, than the reference drug rivastigmine (–6.66/–5.21). Molecular dynamics simulations showed that rivastigmine had the most favourable binding affinity for AChE, while the Schiff bases, B1-B3 outperformed Rivastigmine against BChE with B3 showing the strongest binding affinity (ΔGbind = − 28.10 kcal/mol for AChE and − 26.31 kcal/mol for BChE) further confirming the result from DFT studies. Structural stability analyses revealed that AChE–B2 (RMSD = 1.384 Å, RoG = 22.817 Å) and BChE–B2 (RMSD = 1.619 Å, RoG = 23.211 Å) complexes were particularly stable, indicating that Schiff bases can form stable and energetically favorable interactions comparable to rivastigmine. Therefore, the study identifies B1 - B3 as promising dual cholinesterase inhibitors with favorable physicochemical properties, suggesting their potential as lead candidates for Alzheimer’s disease therapy; however, further in-vitro and in-vivo investigations are essential to validate and confirm their efficacy and safety profiles.