Ethyl nitrobenzoate: A novel scaffold for cholinesterase inhibition

The potential of nitrobenzoate derivatives as cholinesterase inhibitor was highlighted. Compound 2f (the most potent identified in this study) was demonstrated to be a selective acetylcholinesterase inhibitor, although it also inhibits butyrylcholinesterase at higher concentration. In addition, it was found to have low cytotoxicity. Molecular docking on compound 2f was carried out to rationalize the observed in vitro enzymatic assay results. [Display omitted] •Ethyl nitrobenzoate based structure as cholinesterase inhibitor.•Selective AChE inhibition with low cytotoxicity.•Bound to AChE active site via hydrogen bonding and hydrophobic interaction. A series of novel cholinesterase inhibitors containing nitrobenzoate core structure were synthesized by a facile and efficient method. The structure of the novel compounds were fully characterized and confirmed by analytical as well as spectroscopic methods. Compound indicated as 2f was found to possess the best cholinesterase inhibitory activities of all the evaluated compounds. Results suggest that 2f is a selective acetylcholinesterase inhibitor, although it also inhibits butyrylcholinesterase at higher concentration. Kinetics inhibition result suggest that 2f is a mixed-mode inhibitor of acetylcholinesterase. In addition, it was found to have low cytotoxicity. Molecular docking on compound 2f was carried out to rationalize the observed in vitro enzymatic assay results. Most importantly, the potential of nitrobenzoate derivatives as cholinesterase inhibitor was shown through this study. In summary, we discovered nitrobenzoates as a new scaffold that may eventually yield useful compounds in treatment of Alzheimer’s disease.