Isolation, modification, structure-activity relationship (SAR) and molecular docking studies of isoflavones from Derris scandens as potent dual AChE/BuChE inhibitors
摘要
The stems of Derris scandens are rich sources of isoflavonoids including a new isoflavone and nine known isoflavones. Some isolated isoflavones exhibited considerable acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) inhibitory activities. Preliminary SAR studies have indicated that one of the essential structural requirements for a 5,7,4′-trioxygenated isoflavone to exhibit high ChE inhibitory activities is the presence of prenyl group(s). Structural modifications of the isoflavone 5 to ester and ether derivatives did not enhance the ChE inhibitory potential. Molecular docking studies have indicated that, if the isoflavone structure is more flexible, the better binding of isoflavone molecule to the receptor should be achieved. The more flexible dihydro analog of the prenyl moiety was therefore prepared from the isoflavone 5 to give corresponding dihydro analog 19 and the tetrahydro analog 20. It was found that the dihydro analog 19 was the most active analog for AChE and BuChE inhibitions, with the IC50 values of 0.41 ± 0.07 µM and 0.64 ± 0.01µM, respectively. It was 3.3- and 4.8-fold, respectively, more active than galanthamine. In addition, the dihydro analog 19 exhibited lower cytotoxicity toward Vero and RAW 264.7 cells than the isoflavone 5. Molecular docking studies indicated that 19 could simultaneously interact with the PAS, AS and CT of AChE and BuChE. The presence of an isopentyl group on isoflavone ring B is necessary for the dihydro analog to exhibit anti-ChE activity. Hence, an isoflavone with an isopentyl group on ring B, a prenyl group on ring A and suitable hydroxy groups on the aromatic ring could be a possible lead candidate for a dual-target-directed ligand for the treatment of Alzheimer’s disease.