Synthesis, Docking, In vitro and In silico Investigations of novel Tacrine Derivatives as Acetylcholinesterase inhibitors

Abstract

In this paper, we report the synthesis of novel tacrine derivatives with different ring sizes of cyclic ketones and investigate their drug-like properties to identify the lead molecule for treating Alzheimer’s disease (AD). The studies revealed that compound 3c, a tacrine-2-carboxylic ester, binds to the catalytic active site (CAS) of AChE with a glide score of -11.49 kcal/mol and binding energy of -75.04 Kcal/mol. In comparison, tacrine showed a glide score of -10.59 kcal/mol with binding energy of -54.05 kcal/mol. The interaction of tacrine and its derivative at the active site of AChE involves a hydrogen bond between Tyr124 and Ser125, as well as pi-pi stacking and cationic interactions with Trp86. Both tacrine and compound 3c exhibit similar interactions, and protein-ligand binding heavily relies on π-π stacking interactions, which serve as an indicator of the binding enthalpy. Most of the synthesized tacrine derivatives showed a good potency less than 100 nM. of 11 analogues compounds 3c, 3f, 3k and 3m were found to exhibit good potency of 46.61 nM, 45.95 nM, 2.72 nM and 13.60 nM respectively towards inhibition of acetylcholinesterase, respectively. Molecular dynamics simulation confirmed the significant binding of compound 3c with an average RMSD value of 1.36 ± 0.14 Å. So, the compound 3c can be considered as promising hits or lead derivative as a cholinesterase inhibitor for the treatment of Alzheimer’s disease.