Pyrazolamide derivatives inhibit α-Synuclein aggregation, disaggregate preformed fibers, and reduce inclusion formation in neuron cells.

Autor: Xing LZ; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052, Zhengzhou, China., Zhang W; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052, Zhengzhou, China., Zhao YD; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052, Zhengzhou, China., Xu J; Department of Pharmacology, School of Basic Medical Science, Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Kexue Road 100, 450001, Zhengzhou, China. Electronic address: xuji@zzu.edu.cn., Zhang YX; Green Catalysis Center, College of Chemistry, Zhengzhou University, Daxue Road 75, 450052, Zhengzhou, China. Electronic address: zhangyx@zzu.edu.cn.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Mar 15; Vol. 268, pp. 116198. Date of Electronic Publication: 2024 Feb 06.
DOI: 10.1016/j.ejmech.2024.116198
Abstrakt: α-Syn fibers, the primary cause and central element of Lewy bodies (LB), play a pivotal role in the development of Parkinson's disease (PD). This research aims to identify more potent inhibitors of α-Syn aggregation. A series of N-aryl-3-aryl-pyrazole-5-carboxamide derivatives were designed and synthesized for this purpose. Among them, four candidate compounds, combining pyrazole and polyphenol blocks, were identified through screening, demonstrating good inhibitory effects with IC 50 values in the low micromolar range (1.25-4.29 μM). Two candidates exhibited high permeability through the blood-brain barrier. Mechanistic studies using various methods revealed that the candidates preferentially bind to the aggregation-prone domains-proNAC or NAC domains of α-Syn. This binding hinders the conformational transition from random coil/α-helix to β-sheet, preserving α-Syn proteostasis. As a result, it interferes with α-Syn nuclei formation, prolongs the lag phase, decelerates the elongation phase, and ultimately impedes the formation of α-Syn fibrils. Additionally, the candidates demonstrated promising results in the disaggregation of preformed α-Syn fibers, potentially by binding to specific sites near the β-sheet domain within fibers. This reduces fiber stability, causing rapid collapse and yielding smaller aggregates and monomers. Crucially, the candidate compounds exhibited significant inhibitory efficacy against α-Syn aggregation within nerve cells with low cytotoxicity. This resulted in a notable inhibition of the formation of LB-like α-Syn inclusions. These compounds show considerable promise as potential therapeutic agents for the prevention and treatment of PD.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Databáze: MEDLINE
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