Synthesis, docking, <i>in vitro</i> and <i>in silico</i> investigations of novel tacrine derivatives as acetylcholinesterase inhibitors

Different cyclic ketones were used as substrates to synthesize tacrine derivatives to investigate their drug-like properties to identify a lead molecule for treating Alzheimer's disease (AD). The studies revealed that compound 3c, a tacrine-2-carboxylic ester, binds to the catalytically active site (CAS) of AChE with a glide score of -11.49 kcal mol^-1 and binding energy of -75.04 kcal mol^-1. In comparison, tacrine showed a glide score of -10.59 kcal mol^-1 with a binding energy of -54.05 kcal mol^-1. The interaction of tacrine and its derivative at the active site of AChE involves a hydrogen bond between Tyr124 and Ser125, as well as π-π 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 of less than 100 nM. Among the 16 analogues, compounds 3c, 3f, and 3m were found to exhibit good potency of 46.8 nM, 45.9 nM and 13.6 nM, respectively, towards the inhibition of acetylcholinesterase. Molecular dynamics simulation confirmed the significant binding of compound 3c with an average RMSD value of 1.36 ± 0.14 Å. Therefore, compound 3c can be considered as a promising hit or lead derivative as a cholinesterase inhibitor for the treatment of Alzheimer's disease.