Para-Substituted Thiosemicarbazones as Cholinesterase Inhibitors: Synthesis, In Vitro Biological Evaluation, and In...

The current research reports the synthesis of 14 para-substituted thiosemicarbazone derivatives in good to excellent yields using standard procedures. Initially, 4-ethoxybenzaldehyde (1) and 4-nitrobenzaldehyde (2) were refluxed with thiosemicarbazide in the presence of acetic acid in ethanol for 4-5 h. Then, various substituted phenacyl bromides were treated with the desired thiosemicarbazones (3 and 4) in the presence of triethylamine in ethanol with constant stirring for 5-6 h. The resulting derivatives were confirmed through electron impact mass spectrometry and ¹H NMR spectroscopy and evaluated for anticholinesterase inhibitory activity. Among the series, four compounds, 19, 17, 7, and 6, showed potent inhibitory activity against the acetylcholinesterase (AChE) enzyme, having IC₅₀ values of 110.19 ± 2.32, 114.57 ± 0.15, 140.52 ± 0.11, and 160.04 ± 0.02 μM, respectively, compared with standard galantamine (IC₅₀ = 104.5 ± 1.20 μM). Similarly, compounds 19 (IC₅₀ = 145.11 ± 1.03 μM), 9 (IC₅₀ = 147.20 ± 0.09 μM), 17 (IC₅₀ = 150.36 ± 0.18 μM), and 6 (IC₅₀ = 190.21 ± 0.13 μM) were the most excellent inhibitors of butyrylcholinesterase (BChE) when compared with the standard drug galantamine (IC₅₀ = 156.8 ± 1.50 μM). In silico studies were accomplished on the produced derivatives in order to explain the binding interface of compounds with the active sites of AChE and BChE enzymes.