Amide derivatives of Gallic acid: Design, synthesis and evaluation of inhibitory activities against in vitro α-synuclein aggregation

• Published in: Bioorganic & medicinal chemistry 2020-08, Vol.28 (15), p.115596-115596, Article 115596
• Main Authors: Chen, Li, Huang, Guo-Long, Lü, Ming-Huan, Zhang, Yun-Xiao, Xu, Ji, Bai, Su-Ping
• Format: Article
• Language: English
• Subjects: Amide derivatives of Gallic acid; Anti-aggregation; Inhibitor; Synthesis; α-Synuclein
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2020.115596

[Display omitted] Gallic acid (GA), a natural phenolic acid, has received numerous attention because of its anti-oxidative, anti-inflammatory, and anti-cancer activity. More importantly, GA can act as an efficient inhibitor of α-Synuclein (α-Syn) aggregation at early stages. Nevertheless, some evidences suggest that GA is unlikely to cross the blood–brain barrier because of its high hydrophilicity. Hence, GA may not be considered as a promising candidate or entering brain and directly affecting the central nervous system. Accordingly, we have designed and synthesized a series of amide derivatives of GA, some of which possess appropriate lipophilicity and hydrophilicity with LogP (2.09–2.79). Meanwhile, these sheet-like conjugated compounds have good π-electron delocalization and high ability of hydrogen-bond formation. Some compounds have shown better in vitro anti-aggregation activities than GA towards α-Syn, with IC50 down to 0.98 μM. The valid modification strategy of GA is considered an efficient way to discover novel inhibitors of α-Syn aggregation.