In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate <i>N</i>-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound <b>9a</b> (a d-galactose derivative) being the most potent inhibitor (IC<sub>50</sub> = 0.17 μM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (<b>8b</b>; IC<sub>50</sub> = 2.75 μM). Moreover, the <i>in silico</i> ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, <i>in vitro</i> studies demonstrated that the two most potent compounds against BuChE (<b>8b</b> and <b>9a</b>) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.