Synthesis, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities, and molecular docking studies of a novel compound based on combination of flurbiprofen and isoniazide

Abstract

Synthesis of a compound with balanced bioactivities against a specific target is always a challenging task. In this study, a novel compound (1) has been synthesized by combination of flurbiprofen and isoniazide and shows similar to 2.5 times enhanced acetylcholinesterase (AChE) inhibition activity and similar to 1.7 times improved butyrylcholinesterase (BuChE) inhibition activity compared to flurbiprofen and a standard drug (i.e. physostigmine). A comparative AutoDock study has been performed, based on the optimized structure, by the DFT/B3LYP method, which confirmed that compound (1) is more active against AChE and BuChE, with calculated binding energies of -12.9 kcal mol(-1) and -9.8 kcal mol(-1) respectively as compared to flurbiprofen and an eserine (physostigmine) standard for which the binding energy was calculated to be -10.1 kcal mol(-1) and -8.9 kcal mol(-1), respectively. A mixed mode of inhibition of AChE and BuChE with compound 1 was confirmed by Lineweaver-Burk plots. AChE and BuChE inhibition activity alongside docking results suggests that compound (1) could be used for treatment of Alzheimer's disease. Moreover, compound (1) also exhibit better alpha-chymotrypsin activity compared to flurbiprofen. Furthermore, in vitro and in vivo analysis confirmed that compound (1) exhibit more activity and less toxicity than the parent compounds.