2. Academic Validation
  3. Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy

Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer's Disease Therapy

  • ACS Chem Neurosci. 2023 Dec 27. doi: 10.1021/acschemneuro.3c00588.
Shoaib Manzoor 1 2,  Moustafa T Gabr 3,  Mohamed S Nafie 4 5,  Md Kausar Raza 6,  Ashma Khan 7,  Shahid M Nayeem 7,  Reem K Arafa 8 9,  Nasimul Hoda 1
Affiliations

Affiliations

  • 1 Drug Design and Synthesis Laboratory, Department of Chemistry, Jamia Millia Islamia, New Delhi 110025, India.
  • 2 Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
  • 3 Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York10021, United States.
  • 4 Department of Chemistry, College of Sciences, University of Sharjah, Sharjah (P.O. Box 27272), United Arab Emirates.
  • 5 Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
  • 6 Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore 560012, India.
  • 7 Department of Chemistry, Aligarh Muslim University, Aligarh, UP 202002, India.
  • 8 Drug Design and Discovery Lab, Helmy Institute for Medical Sciences, Zewail City of Science, Technology and Innovation, Giza 12578, Egypt.
  • 9 Biomedical Sciences Program, University of Science and Technology, Zewail City of Science, Technology and Innovation, Giza12578,Egypt.
PMID: 38149821 DOI: 10.1021/acschemneuro.3c00588
Abstract

The development of multitargeted therapeutics has evolved as a promising strategy to identify efficient therapeutics for neurological disorders. We report herein new quinolinone hybrids as dual inhibitors of acetylcholinesterase (AChE) and Aβ aggregation that function as multitargeted ligands for Alzheimer's disease. The quinoline hybrids (AM1-AM16) were screened for their ability to inhibit AChE, BACE1, amyloid fibrillation, α-syn aggregation, and tau aggregation. Among the tested compounds, AM5 and AM10 inhibited AChE activity by more than 80% at single-dose screening and possessed a remarkable ability to inhibit the fibrillation of Aβ42 oligomers at 10 μM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving half-maximal AChE inhibitory concentration (IC50) values of 1.29 ± 0.13 and 1.72 ± 0.18 μM, respectively. In addition, AM5 and AM10 demonstrated concentration-dependent inhibitory profiles for the aggregation of Aβ42 oligomers with estimated IC50 values of 4.93 ± 0.8 and 1.42 ± 0.3 μM, respectively. Moreover, the neuroprotective properties of the lead compounds AM5 and AM10 were determined in SH-SY5Y cells incubated with Aβ oligomers. This work would enable future research efforts aiming at the structural optimization of AM5 and AM10 to develop potent dual inhibitors of AChE and amyloid aggregation. Furthermore, the in vivo assay confirmed the antioxidant activity of compounds AM5 and AM10 through increasing GSH, CAT, and SOD activities that are responsible for scavenging the ROS and restoring its normal level. Blood investigation illustrated the protective activity of the two compounds against lead-induced neurotoxicity through retaining hematological and liver enzymes near normal levels. Finally, immunohistochemistry investigation revealed the inhibitory activity of β-amyloid (Aβ) aggregation.

Keywords

Alzheimer’s disease; acetylcholinesterase; amyloid-beta; quinolinone hybrids.

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