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

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 1 H 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 IC 50 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 (IC 50 = 104.5 ± 1.20 μM). Similarly, compounds 19 (IC 50 = 145.11 ± 1.03 μM), 9 (IC 50 = 147.20 ± 0.09 μM), 17 (IC 50 = 150.36 ± 0.18 μM), and 6 (IC 50 = 190.21 ± 0.13 μM) were the most excellent inhibitors of butyrylcholinesterase (BChE) when compared with the standard drug galantamine (IC 50 = 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.