Novel neuroprotective pyromeconic acid derivatives with concurrent anti-Aβ deposition, anti-inflammatory, and anti-oxidation properties for treatment of Alzheimer's disease.

Abstract

We synthesized a series of novel pyromeconic acid-styrene hybrid compounds and measured their activities in inhibiting Aβ1-42 self-aggregation and promoting disaggregation, and their anti-inflammatory and antioxidant properties. The most potent compound, compound 30, had IC50 values of 11.15 μM and 6.87 μM for inhibition of fibril aggregation and promotion of fibril disaggregation, respectively. Because of its redox metal chelating property, 30 also inhibited Cu2+-induced Aβ1-42 fibril aggregation and promoted fibril disaggregation with IC50 of 3.69 μM and 3.35 μM, respectively. Molecular docking demonstrated that 30 interacted with key amino acids of Aβ1-42, and the reliability of the complex was confirmed by molecular dynamics. In addition, 30 displayed excellent antioxidative activity (oxygen radical absorbance capacity = 2.65 Trolox equivalents) and moderate anti-inflammatory activity and neuroprotection in cell culture assays. Compound 30 was safe in acute toxicity test in mice, and it exhibited favorable pharmacokinetic properties, particularly, accumulation in the hippocampus (maximum ratio of hippocampus to plasma = 7.12). Compound 30 alleviated cognitive deficits in scopolamine-induced amnesia mice; this property may have been attributed to reducing neuroinflammation by inhibiting ionized calcium binding adapter molecule 1 and glial fibrillary acidic protein expression and reducing oxidative stress by activating the Nrf2/HO-1 signaling pathway. In view of its many properties, we envision that 30 is a promising lead for the treatment of Alzheimer's disease.

• Authors: Xueyan Liu, Chuanyu Yu, Yuxing Yao, Huifang Lai, Xiaoxia Ye, Jiexin Xu, Jianpeng Guo, Xian Xiao, Chen Lin, Zhihong Huang, Jin Lin, Changxi Yu, Daijun Zha
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 248 Pg. 115120 (Feb 15 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 36682173 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Masson SAS.

Chemical References

• Amyloid beta-Peptides
• pyromeconic acid
• Cholinesterase Inhibitors
• Antioxidants
• Anti-Inflammatory Agents
• Neuroprotective Agents
• Acetylcholinesterase

Topics

• Mice
• Animals
• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (metabolism)
• Molecular Docking Simulation
• Neuroprotection
• Reproducibility of Results
• Cholinesterase Inhibitors (pharmacology)
• Antioxidants (chemistry)
• Oxidation-Reduction
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Neuroprotective Agents (chemistry)
• Acetylcholinesterase (metabolism)