Evaluation of cholinesterase enzyme inhibitory potential of dipterocarpol derivatives

Abstract

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) - are depression and neurodegenerative diseases that target enzymes, including Alzheimer’s disease (AD). With the goal of searching for cholinesterase enzyme inhibitors, a series of four new and twelve previously modified at C2/С2,С21 (arylidenes) and C3 (acylates) positions of dipterocarpol compounds were evaluated for acetylcholinesterase (from electric eel) and butyrylcholinesterase (from equine serum) inhibitory activity. As a result, dammaranes with 3β-O-(2-furoyl)- 2, 2-(p-nitro-benzylidene)- 7, and 2,21-bis-(p-carbonylbenzylidene)- 17 fragments exhibited a pronounced activity with 79.0, 68.8 and 75.2% inhibition of AChE, but were less active for BChE. The structure-activity relationship indicated that the type of substituents in the arylidene or ester moiety and the structure of the side chain of dammarane scaffold play an important role in the inhibition of AChE. Extra experiments showed them as mixed-type inhibitors with K_i 5.99 (for 2), 2.43 (for 7) and 0.51 µM (for 17). Molecular docking studies showed that compounds 2, 7, and 17 have the highest binding scores −8.4, −8.9, and −8.7 kcal/mol, respectively. There are revealed key interactions and confirmed successful placement of the compounds 2, 7, and 17 in the active site of AChE, that elucidate these inhibitory effects.