Pharmacological Investigations of Selected Multitarget‐Direct Ligands for the Treatment of Alzheimer's Disease

Manzoor, Shoaib; Prajapati, Santosh Kumar; Majumdar, Shreyasi; Khurana, Shilpi; Krishnamurthy, Sairam; Hoda, Nasimul

doi:10.1002/slct.202200975

Cited by 2 publications

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References 42 publications

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“…Accumulating evidence indicates that amyloid oligomers are the primary cause of neurotoxicity and continuously stimulate inflammatory mediators. In addition, Aβ 1–42 exhibits a high propensity to create fibrils and serves as an oxygen-free radical donor that produces reactive oxygen species (ROS) and influences the overall physiological function of neuronal cells. , Therefore, the inhibition of amyloid aggregation by designing inhibitors is one of the attractive approaches to decrease the accumulation of Aβ and toxicity in the AD brain. − …”

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confidence: 99%

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

Manzoor,

Gabr,

Nafie

et al. 2023

ACS Chem. Neurosci.

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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 Aβ 42 oligomers at 10 μM. In addition, dose-dependent screening of AM5 and AM10 was performed, giving halfmaximal AChE inhibitory concentration (IC 50 ) 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 Aβ 42 oligomers with estimated IC 50 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.

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