Yang_2024_Mol.Divers__

The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and synthesized by introducing carbamate groups. The crystal structure of 1 was analyzed by X-ray diffraction, which showed a large conjugated coplanar structure and might be favorable for the insertion into the Abeta folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Abeta aggregation ability of 1-5. The results showed that 1-5 had good cholinesterase inhibitory activities. Compound 4 showed the highest inhibitory activities against butyrylcholinesterase (IC(50) = 0.0760 microM). Further kinetic experiments and molecular docking studies showed that 4 could bind well to butyrylcholinesterase. The molecular dynamics simulations also signified that compared with diosmetin, 4 could reduce the flexibility of the butyrylcholinesterase protein skeleton to a greater extent, and thus had a better inhibitory effect. In addition, 1-5 could selectively chelate copper ions and all of them had good antioxidant activity as well as anti-Abeta aggregation ability. Among them, 4 had the strongest activity to inhibit Cu(2+)-induced Abeta aggregation (51.09%) and had low cytotoxicity. In addition, in vivo ROS activity assay (Caenorhabditis elegans) showed that 4 had the ability to scavenge ROS. Besides, the in vivo Abeta aggregation assay showed that 4 could reduce Abeta aggregation. In conclusion, 4 has the potential to be developed into a multifunctional anti-AD drug.