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

Manzoor, S and Gabr, MT and Nafie, MS and Raza, MK and Khan, A and Nayeem, SM and Arafa, RK and Hoda, N (2023) Discovery of Quinolinone Hybrids as Dual Inhibitors of Acetylcholinesterase and Aβ Aggregation for Alzheimer�s Disease Therapy. In: ACS Chemical Neuroscience .

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Official URL: https://doi.org/10.1021/acschemneuro.3c00588


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. © 2023 American Chemical Society

Item Type: Journal Article
Publication: ACS Chemical Neuroscience
Publisher: American Chemical Society
Additional Information: The copyright for this article belongs to American Chemical Society.
Department/Centre: Division of Chemical Sciences > Inorganic & Physical Chemistry
Date Deposited: 04 Mar 2024 10:02
Last Modified: 04 Mar 2024 10:02
URI: https://eprints.iisc.ac.in/id/eprint/84074

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