Design, synthesis, cholinesterase inhibition and molecular modelling study of novel tacrine hybrids with carbohydrate derivatives

摘要

A series of hybrids containing tacrine linked to carbohydrate-based moieties, such asd-xylose,d-ribose, andd-galactose derivatives, were synthesized by the nucleophilic substitution between 9-aminoalkylamino-1,2,3,4-tetrahydroacridines and the corresponding sugar-based tosylates. All compounds were found to be potent inhibitors of both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the nanomolar IC50scale. Most of thed-xylose derivatives (6a-e) were selective for AChE and the compound6e(IC50?=?2.2?nM for AChE and 4.93?nM for BuChE) was the most active compound for both enzymes. Thed-galactose derivative8awas the most selective for AChE exhibiting an IC50ratio of 7.6 for AChE over BuChE. Only two compounds showed a preference for BuChE, namely7a(d-ribose derivative) and6b(d-xylose derivative). Molecular docking studies indicated that the inhibitors are capable of interacting with the entire binding cavity and the main contribution of the linker is to enable the most favorable positioning of the two moieties with CAS, PAS, and hydrophobic pocket to provide optimal interactions with the binding cavity. This finding is reinforced by the fact that there is no linear correlation between the linker size and the observed binding affinities. The majority of the new hybrids synthesized in this work do not violate the Lipinski's rule-of-five according to FAF-Drugs4, and do not demonstrated predicted hepatotoxicity according ProTox-II.