Design, Synthesis, and Evaluation of Acetylcholinesterase and Butyrylcholinesterase Dual-Target Inhibitors against Alzheimer’s Diseases

Abstract

A series of novel compounds <b>6a</b>-<b>h</b>, <b>8i</b>-<b>1</b>, <b>10s</b>-<b>v</b>, and <b>16a</b>-<b>d</b> were synthesized and evaluated, together with the known analogs <b>11a</b>-<b>f</b>, for their inhibitory activities towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The inhibitory activities of AChE and BChE were evaluated <i>in vitro</i> by Ellman method. The results show that some compounds have good inhibitory activity against AChE and BChE. Among them, compound <b>8i</b> showed the strongest inhibitory effect on both AChE (eeAChE IC₅₀ = 0.39 μM) and BChE (eqBChE IC₅₀ = 0.28 μM). Enzyme inhibition kinetics and molecular modeling studies have shown that compound <b>8i</b> bind simultaneously to the peripheral anionic site (PAS) and the catalytic sites (CAS) of AChE and BChE. In addition, the cytotoxicity of compound <b>8i</b> is lower than that of Tacrine, indicating its potential safety as anti-Alzheimer's disease (anti-AD) agents. In summary, these data suggest that compound <b>8i</b> is a promising multipotent agent for the treatment of AD.