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(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 Aβ 1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics. [Display omitted] • A series of chrysin derivatives were designed and synthesized. • 1 – 4 show potent antioxidative, Aβ 1–42 disaggregation, selective anti-ChE activities. • The single crystal of 1 −Cu(II) was prepared and X-ray diffracted for the first time. • X-ray analysis provides a reliable structure-activity insight at the molecular level. • 1 – 4 have high BBB permeability and bioavailability and 1 has low cell toxicity. [ABSTRACT FROM AUTHOR]