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Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer’S Disease Publisher



Noori M1 ; Khalili Ghomi M2 ; Dastyafteh N1 ; Oliyaei N3 ; Hamedifar H4, 5 ; Javanshir S1 ; Tanideh N3 ; Sattarinezhad E6 ; Sattari F7 ; Haghani M10 ; Rahmani H8 ; Larijani B2 ; Mahdavi M2 ; Hajimiri MH4, 5 Show All Authors
Authors
  1. Noori M1
  2. Khalili Ghomi M2
  3. Dastyafteh N1
  4. Oliyaei N3
  5. Hamedifar H4, 5
  6. Javanshir S1
  7. Tanideh N3
  8. Sattarinezhad E6
  9. Sattari F7
  10. Haghani M10
  11. Rahmani H8
  12. Larijani B2
  13. Mahdavi M2
  14. Hajimiri MH4, 5
  15. Iraji A9

Source: ACS Omega Published:2024


Abstract

An Isoindolinedione-benzamide pyridinium derivatives were designed through a structure-based strategy and synthesized as novel multifunctional anti-Alzheimer agents. The inhibitory activities of all 17 derivatives against acetylcholinesterase and butyrylcholinesterase were evaluated. Results exhibited that compound 7j displayed promising AChE inhibitory activity with an IC50 value of 0.26 ± 0.07 μM, and compound 7c exhibited an IC50 value of 0.08 ± 0.01 μM against BChE with 132-fold better inhibitory activity in comparison with positive control. Next, the enzyme kinetics studies and detailed binding mode via molecular docking were performed for the most potent compounds. Additionally, molecular dynamics simulations were accomplished to further investigate the potent compound’s interaction, orientation, and conformation over the related enzymes. The neurotoxicity of the most potent derivative was executed against SH-SY5Y, and the mRNA levels of GSK-3α and GSK-3β after treatment with 7c on SH-SY5Y were evaluated. Results exhibited the mRNA levels of GSK-3β were decreased compared to the control group. All these results indicate that 7c is a good starting point for developing a multifunctional anti-Alzheimer compound. © 2024 The Authors. Published by American Chemical Society.
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