Synthesis of new lophine–carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling. Issue 12 (8th November 2019) - Lopes, João Paulo Bizarro
Abstract : A series of selective butyrylcholinesterase inhibitors were obtained. The absence of in vitro cytotoxicity and good ADME-Tox profile make these compounds new promising prototypes for the treatment of Alzheimer's disease. Abstract : 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 N -alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d -galactose derivative) being the most potent inhibitor (IC50 = 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 (8b ; IC50 = 2.75 μM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a ) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.