Study on the novel usnic acid derivatives: Design, synthesis, X-Ray crystal structure of Cu(II) complex and anti-AD activities

• Published in: Journal of molecular structure Vol. 1263; p. 133018
• Main Authors: Yang, Aihong, Liu, Wenjing, Li, Xiangyu, Wu, Wanru, Kou, Xiaodi, Shen, Rui
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.09.2022
• Subjects: Alzheimer's disease; Antioxidant activity; Metal chelation ability; Usnic acid derivatives; Metal chelation ability; Usnic acid derivatives; Alzheimer's disease; Antioxidant activity
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.133018

•4 derivatives were obtained by structural modification of the “triketone” moiety of UA.•The single crystal of the Cu(II) complex of the hydrolyzed mono-substituted 4 was obtained.•Derivatives 1–4 had much better antioxidant and anti-cholinesterase activities than UA.•Derivatives 1–4 had good metal chelating abilities.•The metal complexes of derivatives also have good anti-AD and anti-oxidative activities. More and more evidence suggested that bio-metals including iron, zinc and copper play an important role in Alzheimer's disease (AD). Metal chelation agents may play an important role through promoting the metal homeostasis for AD treatment. In this study, UA (usnic acid), a natural product with antioxidant activity and metal chelation sites was selected as a lead compound. Different types of tertiary amine groups were introduced to synthesize four UA derivatives 1–4 as metal chelators and cholinesterase inhibitors since tertiary amine moiety was the key pharmacophore to inhibit cholinesterase. And the related activities such as antioxidant, anti-cholinesterase and metal chelation were evaluated. Results showed that 1–4 displayed excellent anti-oxidant activity, with lowest IC50 of 0.433 µM for ·OH scavenging ability and 8.808 µM for ·O2− scavenging ability. The mechanisms of anti-oxidant activities were furtherly studied by cyclic voltammetry. Besides, 1–4 also showed good anti-cholinesterase activities with lowest IC50 of 0.269 µM for acetylcholinesterase (AChE) and 0.361 µM for butyrylcholinesterase (BuChE). The results of molecular docking with AChE and BuChE were consistent with the experimental results. 1–4 displayed obvious chelating abilities with Cu(II) and Fe(III) by UV–vis spectra analysis and the metal complexes also showed good anti-AD activities. Interestingly, single crystal of Cu(II) complex of the hydrolyzed mono-substituted ligand was obtained which further substantiated the metal binding ability and provided clues to the anti-AD activities of the metal complex. Meanwhile, hydrolysis ratio of 4 was also tested by HPLC. Finally, BBB permeability of 1–4 was acceptable by ADMET prediction. Overall, these findings demonstrated that compounds 1–4 might be considered as potential candidates in the anti-AD therapy. Four derivatives (1–4) of UA had excellent metal chelating, antioxidant and anti-cholinesterase activities related AD. The single crystal of the Cu(II) complex of the hydrolyzed mono-substituted 4 was obtained and the metal complexes also have good anti-AD activities. [Display omitted]