A multifunctional anti-AD approach: Design, synthesis, X-ray crystal structure, biological evaluation and molecular docking of chrysin derivatives

With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by ¹H NMR, ¹³C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on Reactive Oxygen Species, Aβ_1-42 aggregation (self-, Cu²⁺-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu²⁺, Fe²⁺, Zn²⁺ and Al³⁺ ions, while had no chelating ability to Other biometals. The copper complexes also showed good AChE, BuChE and Reactive Oxygen Species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(C₁₉H₁₈NO₄)₂] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aβ_1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.