Synthesis, characterization, molecular docking, dynamics simulations, and in silico absorption, distribution, metabolism, and excretion (ADME) studies of new thiazolylhydrazone derivatives as butyrylcholinesterase inhibitors

Abstract In this study, two novel series of thiazolylhydrazone derivatives containing 4-ethylpiperazine (3a–3f) and 4-methoxyphenylpiperazine (3g–3l) side chains were synthesized and their structures were characterized by spectral (1H NMR, 13C NMR, and MS spectra) analyses. In vitro inhibitory activities of synthesized compounds against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined by Ellman method. According to the results, all compounds showed a weak inhibitory effect on AChE, while promising results were obtained on BChE. Among the synthesized compounds, the activities of the derivatives carrying 4-ethylpiperazine (3a–3f) structure were found to be more effective than the compounds carrying 4-methoxyphenyl piperazine (3g–3l) derivatives. Especially, compound 3f bearing the nitro substituent was found to be the most promising compound on BChE in the series. The absorption, distribution, metabolism, and excretion (ADME) parameters of the synthesized compounds were predicted by using the SwissADME server. The potential binding mode and stability of compound 3f with BChE were investigated by the molecular docking and dynamics simulations. The results showed that 3f was strongly bound up with BChE with the optimal conformation; in addition, their binding free energy reached −167.936 ± 13.109 kJ/mol.