New tetrahydro-isoquinoline derivatives as cholinesterase and α-glycosidase inhibitors: Synthesis, characterization, molecular docking & dynamics, ADME prediction, in vitro cytotoxicity and enzyme inhibition studies

In the presented work, it was reported about the synthesis procedure of new isoquinoline derivatives starting from chalcones and acetoacetanilide, a multi-step synthesis pathway yielded four isoquinoline derivatives (5a-d). At the first stage of our research, corresponding cyclohexanone derivatives are synthesized from the Michael addition reaction of chalcones with acetoacetanilide. After that, on the based cyclohexanone derivative was obtained novel isoquinoline derivatives. According to the structures, a plausible reaction mechanism was suggested. The structure of the synthesized compounds was confirmed by NMR spectroscopy method and X-Ray analysis. Additionally, to determine cholinesterase and α-glycosidase inhibition activity compounds 5(a-d) were tested against AChE, BChE and α-Gly as in vitro. In this work, the novel isoquinoline derivatives 5(a-d) demonstrated encouraging inhibitory action against α-glucosidase, as seen by their IC50 values ranging from 9.95 to 19.25 nM. This indicates that they were approximately 1–3 times more active than acarbose (IC50 = 23.07 nM). Also, the molecular docking IFD XP Gscores, dynamics simulations and MM-GBSA ΔG binding free energies of the isoquinoline derivatives on hAChE, hBChE and α-Gly are determined. The molecular dynamics (MD) simulations conducted in this study provided valuable insights into the dynamic behaviors, stabilities, and interaction profiles of ligand–protein complexes involving the R and S isomers of compounds 5c-hAChE, 5c-hBChE, and 5a-αGly. The MD simulations were crucial for understanding the complex stabilities and dynamic mechanisms of the ligand–protein interactions, shedding light on the potential inhibitory roles of these compounds.