Isolation, derivatization, in-vitro, and in-silico studies of potent butyrylcholinesterase inhibitors from Berberis parkeriana Schneid.

ABSTRACT

Seven known isoquinoline alkaloids 1-7 were isolated from the root extracts of Berberis parkeriana Schneid. Nine new derivatives 8-16 of one of the isolated compounds, jatrorrhizine (7), were synthesized. All the isolated as well as derivatized compounds were evaluated for their in-vitro acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity. Functionalized compounds selectively exhibited a potent-to-moderate activity with IC50 = 5.5 ± 0.3-124.5 ± 0.4 µM against butyrylcholinesterase enzyme. Among them, compound 15 was a potent BChE inhibitor (IC50 = 5.5 ± 0.3 µM), as compared to the standard drug galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Active compounds were further subjected to kinetic, and molecular docking studies to predict their modes of inhibition, and interactions with the receptor (BChE), respectively. Enzyme kinetics studies showed that compounds 9 (IC50 = 25.3 ± 0.5 µM), and 14 (IC50 = 23.9 ± 0.5 µM) were non-competitive inhibitors, while compound 15 exhibited a competitive inhibition. In addition, these compounds were found to be non-cytotoxic against human fibroblast (BJ) cell line, except 9 (IC50 = 17.1 ± 1.0 µM), and 10 (IC50 = 18.4 ± 0.3 µM). Inhibition of cholinesterases is an important approach for development of drugs against Alzheimer's disease, and thus discoveries presented here deserve further investigation.