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  3. Synthesis, biological evaluation and molecular modeling studies of methyl indole-isoxazole carbohydrazide derivatives as multi-target anti-Alzheimer's agents

Synthesis, biological evaluation and molecular modeling studies of methyl indole-isoxazole carbohydrazide derivatives as multi-target anti-Alzheimer's agents

  • Sci Rep. 2024 Sep 10;14(1):21115. doi: 10.1038/s41598-024-71729-0.
Aida Iraji 1 2,  Parisa Nikfar 3,  Mohammad Nazari Montazer 4,  Mona Karimi 5,  Najmeh Edraki 6,  Mina Saeedi 7 8,  Seyedeh Sara Mirfazli 9
Affiliations

Affiliations

  • 1 Department of Persian Medicine, School of Medicine, Research Center for Traditional Medicine and History of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 2 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran.
  • 4 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 5 Department of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran.
  • 6 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 7 Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. m-saeedi@tums.ac.ir.
  • 8 Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran. m-saeedi@tums.ac.ir.
  • 9 Department of Medicinal Chemistry, School of Pharmacy, Iran University of Medical Sciences, Tehran, Iran. saramirfazli@gmail.com.
PMID: 39256495 DOI: 10.1038/s41598-024-71729-0
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, 1H NMR, and 13C 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.

Keywords

Acetylcholinesterase; BACE1; Butyrylcholinesterase; Indole; Isoxazole; Molecular dynamic; Synthesis.

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