Synthesis and molecular docking study of thiophene-bearing thiourea derivatives as potential acetylcholinesterase, and butyrylcholinesterase inhibitors

A new series of thiophene-bearing thiourea derivatives (1–11) were synthesized and characterized through ¹³C NMR, ¹H NMR and HR-EIMS. The synthesized derivatives were screened against acetylcholinesterase, and butyrylcholinesterase inhibitory potentials. All derivatives display a variable degree of inhibitory potential ranging from 0.40 ± 0.05 to 26.40 ± 0.40 µM (against AChE) and 1.80 ± 0.10 to 36.80 ± 0.90 µM (against BuChE) as compared to standard drug donepezil (IC₅₀ = 2.16 ± 0.12 µM and 4.5 ± 0.11 µM, respectively). In both cases, among the series analogues 3, 5, 7, 9, and 10 showed many folds better activity than standard drug donepezil. Structure-activity relationship has been also established for all newly synthesized compounds, mainly based on substitution patterns on the phenyl ring. The binding interaction of the most active derivatives with the active site of enzymes was confirmed through a molecular docking study. To evaluate the stability of the protein-ligand complexes 10 ns MD simulation was carried out. The most potent compound such as compound 3 revealed great stability during the 10 ns simulation.