Usnic Acid Derivatives as Multi‐Target Anti‐Alzheimer's Disease Agents: Design, Synthesis, X‐Ray Single Crystal Structure of Zn(II) Complex and Biological Activities

Abstract Alzheimer's disease (AD) is multifactorial, which makes the design of multi‐target‐directed ligands an attractive strategy for the development of anti‐AD drugs. In order to enhance the anti‐AD effects and reduce the toxicity, two usnic acid (UA) derivatives ( 1–2 ) were designed, synthesized and fully characterized by introducing dimethylamine Schiff base moiety into the toxic “triketone” portion. Ellman's method and molecular docking were used to test the cholinesterase inhibitory activities. Antioxidant activities were studied with Fenton reaction, cyclic voltammetry and C. elegans . The results showed that compared with UA, 1–2 had stronger anti‐cholinesterase activities and similar antioxidant activities. Notably, solvent evaporation of 2 and ZnCl 2 formed a single crystal, which was revealed to be a Zn(II) complex with UA and tertiary amine as mixed ligands by X‐ray diffraction. The hydrolysis of 2 was thus furtherly studied by HPLC. Furthermore, the crystal structure supported the replacement of toxic “triketone” moiety in the chelation process, playing a detoxifying role and at the same time regulating metal homeostasis. In silico prediction also showed low hepatotoxicity and acceptable drug‐likeness of 1–2 . Overall, this work provided useful insights into multi‐target anti‐AD candidates with the natural product UA as the lead compound.