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
  • 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: [email protected].
  • 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: [email protected].
  • 5. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: [email protected].
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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