Title : Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer's Disease - Noori_2024_ACS.Omega_9_48032 |
Author(s) : Noori M , Khalili Ghomi M , Dastyafteh N , Oliyaei N , Hamedifar H , Javanshir S , Tanideh N , Sattarinezhad E , Sattari F , Haghani M , Rahmani H , Larijani B , Mahdavi M , Hajimiri MH , Iraji A |
Ref : ACS Omega , 9 :48032 , 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 IC(50) value of 0.26 +/- 0.07 microM, and compound 7c exhibited an IC(50) value of 0.08 +/- 0.01 microM 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-3alpha and GSK-3beta after treatment with 7c on SH-SY5Y were evaluated. Results exhibited the mRNA levels of GSK-3beta 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. |
PubMedSearch : Noori_2024_ACS.Omega_9_48032 |
PubMedID: 39676969 |
Noori M, Khalili Ghomi M, Dastyafteh N, Oliyaei N, Hamedifar H, Javanshir S, Tanideh N, Sattarinezhad E, Sattari F, Haghani M, Rahmani H, Larijani B, Mahdavi M, Hajimiri MH, Iraji A (2024)
Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer's Disease
ACS Omega
9 :48032
Noori M, Khalili Ghomi M, Dastyafteh N, Oliyaei N, Hamedifar H, Javanshir S, Tanideh N, Sattarinezhad E, Sattari F, Haghani M, Rahmani H, Larijani B, Mahdavi M, Hajimiri MH, Iraji A (2024)
ACS Omega
9 :48032