1. Synthesis, biological evaluation and molecular modeling studies of methyl indole-isoxazole carbohydrazide derivatives as multi-target anti-Alzheimer's agents.
- Author
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Iraji A, Nikfar P, Nazari Montazer M, Karimi M, Edraki N, Saeedi M, and Mirfazli SS
- Subjects
- Humans, Molecular Docking Simulation, Isoxazoles chemistry, Isoxazoles pharmacology, Isoxazoles chemical synthesis, Structure-Activity Relationship, Amyloid Precursor Protein Secretases antagonists & inhibitors, Amyloid Precursor Protein Secretases metabolism, Models, Molecular, Binding Sites, Molecular Dynamics Simulation, Aspartic Acid Endopeptidases antagonists & inhibitors, Aspartic Acid Endopeptidases metabolism, Kinetics, Hydrazines, Cholinesterase Inhibitors pharmacology, Cholinesterase Inhibitors chemical synthesis, Cholinesterase Inhibitors chemistry, Alzheimer Disease drug therapy, Alzheimer Disease metabolism, Acetylcholinesterase metabolism, Acetylcholinesterase chemistry, Butyrylcholinesterase metabolism, Butyrylcholinesterase chemistry, Indoles chemistry, Indoles pharmacology, Indoles chemical synthesis
- Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the elderly population globally and there is an urgent demand for developing novel anti-AD agents. In this study, a new series of indole-isoxazole carbohydrazides were designed and synthesized. The structure of all compounds was elucidated using spectroscopic methods including FTIR,
1 H NMR, and13 C NMR as well as mass spectrometry and elemental analysis. All derivatives were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Out of all synthesized compounds, compound 5d exhibited the highest potency as AChE inhibitor with an IC50 value of 29.46 ± 0.31 µM. It showed significant selectivity towards AChE, with no notable inhibition against BuChE. A kinetic study on AChE for compound 5d indicated a competitive inhibition pattern. Also, 5d exhibited promising BACE1 inhibitory potential with an IC50 value of 2.85 ± 0.09 µM and in vitro metal chelating ability against Fe3+ . The molecular dynamic studies of 5d against both AChE and BACE1 were executed to evaluate the behavior of this derivative in the binding site. The results showed that the new compounds deserve further chemical optimization to be considered potential anti-AD agents., (© 2024. The Author(s).)- Published
- 2024
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