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

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.

Microwave-Assisted Organic Synthesis, structure-activity relationship, kinetics and molecular docking studies of non-cytotoxic benzamide derivatives as selective butyrylcholinesterase inhibitors.

A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH3, -OC2H5, and -NO2) was synthesized using an economic, and facile Microwave-Assisted Organic Synthesis, and evaluated for acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) activity in vitro. Structure-activity relationship showed that the substitution of -Br group influenced the inhibitory activity against BCHE enzyme. Synthesized compounds were found to be selective inhibitors of BCHE. In addition, all compounds 1-12 were found to be non-cytotoxic, as compared to the standard cycloheximide (IC50 = 0.8 ±â€¯0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC50 = 0.8 ±â€¯0.6 µM) when compared with the standard galantamine hydrobromide (IC50 = 40.83 ±â€¯0.37 µM). Enzyme kinetic studies indicated that compounds 1, 3-4, and 7-8 showed a mixed mode of inhibition against BCHE, while compounds 2, 5-6 and 9 exhibited an uncompetitive pattern of inhibition. Molecular docking studies further highlighted the interaction of these inhibitors with catalytically important amino acid residues, such as Glu197, Hip438, Phe329, and many others.