2. Academic Validation
  3. Discovery of styrylaniline derivatives as novel alpha-synuclein aggregates ligands

Discovery of styrylaniline derivatives as novel alpha-synuclein aggregates ligands

  • Eur J Med Chem. 2021 Dec 15;226:113887. doi: 10.1016/j.ejmech.2021.113887.
Jiang Bian 1,  Yi-Qi Liu 2,  Jie He 1,  Xin Lin 1,  Chen-Yang Qiu 1,  Wen-Bo Yu 2,  Yan Shen 2,  Ze-Yun Zhu 1,  De-Yong Ye 3,  Jian Wang 4,  Yong Chu 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: dyye@shmu.edu.cn.
  • 4 Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, 200040, China. Electronic address: wangjian_hs@fudan.edu.cn.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: cy110@fudan.edu.cn.
PMID: 34624824 DOI: 10.1016/j.ejmech.2021.113887
Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Early diagnosis is the key to treatment but is still a great challenge in the clinic now. The discovery of alpha-synuclein (α-syn) aggregates ligands has become an attractive strategy to meet the early diagnosis of PD. Herein, we designed and synthesized a series of styrylaniline derivatives as novel α-syn aggregates ligands. Several compounds displayed good potency to α-syn aggregates with Kd values less than 0.1 μM. The docking study revealed that the hydrogen bonds and cation-pi interaction between ligands and α-syn aggregates would be crucial for the activity. The representative compound 7-16 not only detected α-syn aggregates in both SH-SY5Y cells and brain tissues prepared from two kinds of α-syn preformed-fibrils-injected mice models but also showed good blood-brain barrier penetration characteristics in vivo with a brain/plasma ratio over 1.0, which demonstrates its potential as a lead compound for further development of in vivo imaging agents.

Keywords

Blood-brain barrier; Early diagnosis; Parkinson's disease; Styrylphenyl benzamides; α-synuclein ligand.

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