Yang_2022_Eur.J.Med.Chem_233_114216

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 (1)H NMR, (13)C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Abeta(1-42) aggregation (self-, Cu(2+)-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 Cu(2+), Fe(2+), Zn(2+) and Al(3+) 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(C(19)H(18)NO(4))(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 Abeta(1-42) disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.