2. Academic Validation
  3. Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3β level targeting Alzheimer's disease

Phenyl-quinoline derivatives as lead structure of cholinesterase inhibitors with potency to reduce the GSK-3β level targeting Alzheimer's disease

  • Int J Biol Macromol. 2023 Oct 11;253(Pt 7):127392. doi: 10.1016/j.ijbiomac.2023.127392.
Milad Noori 1,  Navid Dastyafteh 2,  Sajedeh Safapoor 3,  Minoo Khalili Ghomi 3,  Romina Tanideh 4,  Kamiar Zomorodian 5,  Haleh Hamedifar 6,  Mahintaj Dara 4,  Shahrokh Zare 4,  Cambyz Irajie 7,  Shahrzad Javanshir 2,  Hossein Rastegar 8,  Nikoo Panahi 9,  Bagher Larijani 3,  Mohammad Mahdavi 3,  Mir H Hajimiri 10,  Aida Iraji 11
Affiliations

Affiliations

  • 1 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, Iran; Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 2 Pharmaceutical and Heterocyclic Chemistry Research Laboratory, Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.
  • 3 Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
  • 4 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 5 Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 6 CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran; CinnaGen Research and Production Co., Alborz, Iran.
  • 7 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
  • 8 Food and Drug Research Institute, Food and Drug Administration, MOHE, Tehran, Iran.
  • 9 Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Science.
  • 10 CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran; CinnaGen Research and Production Co., Alborz, Iran. Electronic address: [email protected].
  • 11 Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: [email protected].
PMID: 37827412 DOI: 10.1016/j.ijbiomac.2023.127392
Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to cognitive decline and memory loss. Unfortunately, there is no effective treatment for this condition, so there is a growing interest in developing new anti-AD agents. In this research project, a series of phenyl-quinoline derivatives were designed as potential anti-AD agents. These derivatives were substituted at two different positions on benzyl and phenyl rings. The structures of the derivatives were characterized using techniques such as IR spectroscopy, 1H NMR, 13C NMR, and elemental analysis. During the in vitro screening, the derivatives were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). It was observed that most of the derivatives showed higher selectivity against BChE compared to AChE. Among the derivatives, analog 7n (with a methoxy group at R1 and a 4-bromine substituent at R2 exhibited the highest potency, with a 75-fold improvement in the activity compared to the positive control. Importantly, this potent analog demonstrated no toxicity at the tested concentration on SH-SY5Y cells, indicating its potential as a safe anti-AD agent. The level of GSK-3β was also reduced after treatments with 7n at 50 μM. Overall, this study highlights the design and evaluation of phenyl-quinoline derivatives as promising candidates for developing novel anti-AD agents.

Keywords

AChE; BChE; GSK-3β; Molecular dynamic simulations; Phenyl-quinoline.

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