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

Bioorganic & Medicinal Chemistry
2019.0

Abstract

A series of benzamide derivatives 1-12 with various functional groups (-H, -Br, -F, -OCH<sub>3</sub>, -OC<sub>2</sub>H<sub>5</sub>, and -NO<sub>2</sub>) 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 (IC<sub>50</sub> = 0.8 ± 0.2 µM). Among them, compound 3 revealed the most potent BCHE inhibitory activity (IC<sub>50</sub> = 0.8 ± 0.6 µM) when compared with the standard galantamine hydrobromide (IC<sub>50</sub> = 40.83 ± 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.

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