Butyrylcholinesterase is an enzyme whose concentration increases significantly with the progress of the Alzheimer's disease, which makes it a promising drug target in the late stages of the disease. In order to understand and improve the properties of a selective BChE inhibitor, compound 2, we performed a structural manipulation of the benzyl moiety. We thus replaced the benzyl moiety with p-F, m-F, p-CN, m-CN and p-NMe2 benzyl moiety and evaluated the properties of the new compounds. All compounds are selective BChE inhibitors and mainly exert their inhibition in nanomolar concentration range. Compound 4 is the most active (IC50 = 49.1 nM) while compound 5 is the least active BChE inhibitor (IC50 = 1463.9 nM). Both of these activities are lower than IC50 of the initial compound 2, being 7.2 nM. Designed and synthesized compound were also evaluated on the basis of their theoretical pharmacokinetic properties. The analysis showed that all the compounds, including compound 2, have appropriate pharmacokinetic properties and are thus likely to cross both the gastrointestinal tract and the blood-brain barrier. Compound 2 remains a promising compound in the development of novel BChE inhibitors and the obtained information about the influence of the substituted benzyl moiety on compound’s performance can be used in further structural optimization of the compound 2.
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