Isoindolinedione-Benzamide Pyridinium Derivatives for Targeting Alzheimer's Disease.

Autor: Noori M; Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran., Khalili Ghomi M; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran 1416634793, Iran., Dastyafteh N; Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran., Oliyaei N; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran., Hamedifar H; CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj 1461965381, Iran.; CinnaGen Research and Production Co., Alborz 3164819712, Iran., Javanshir S; Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran 16846-13114, Iran., Tanideh N; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran., Sattarinezhad E; Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran., Sattari F; Student Research Committee, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran., Haghani M; Department of Physiology, The Medical School, Shiraz University of Medical Sciences, Shiraz 71348-14336, Iran., Rahmani H; Department of Health Management, Policy and Economics, School of Public Health, Tehran University of Medical Sciences, Tehran 1416634793, Iran., Larijani B; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran 1416634793, Iran., Mahdavi M; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran 1416634793, Iran., Hajimiri MH; CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj 1461965381, Iran.; CinnaGen Research and Production Co., Alborz 3164819712, Iran., Iraji A; Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran.
Jazyk: angličtina
Zdroj: ACS omega [ACS Omega] 2024 Nov 25; Vol. 9 (49), pp. 48032-48043. Date of Electronic Publication: 2024 Nov 25 (Print Publication: 2024).
DOI: 10.1021/acsomega.4c04027
Abstrakt: 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 μM, and compound 7c exhibited an IC 50 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.
Competing Interests: The authors declare no competing financial interest.
(© 2024 The Authors. Published by American Chemical Society.)
Databáze: MEDLINE
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