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

Abstract

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.

The Effect of Metal Ions (Fe, Co, Ni, and Cu) on the Molecular-Structural, Protein Binding, and Cytotoxic Properties of Metal Pyridoxal-Thiosemicarbazone Complexes

“…Quang and coworkers investigated the thiosemicarbazone quantum dots for treating Alzheimer's disease by in silico modeling [16], thus showing the importance of theoretical methods for preparing smallmolecular-weight pharmaceuticals. The inhibition of cholinesterase by the para-substituted thiosemicarbazones was analyzed in vitro and in silico in the paper by Khan and coworkers [17]. Some of the thiosemicarbazone ligands (marboran or triapine) and their metal complexes have been used in medical practice [18].…”

Green synthesis, biological and molecular docking of some novel sulfonamide thiadiazole derivatives as potential insecticidal against Spodoptera littoralis

“…Acetylcholinesterase (AChE) inhibitors are a class of drugs that can enhance the levels of acetylcholine, a neurotransmitter involved in memory and cognition, by preventing its breakdown by the enzyme AChE. Various class of compounds have been newly reported as an acetyl cholinesterase inhibitors 11 – 13 . AChE inhibitors are used to treat Alzheimer’s disease, a neurodegenerative disorder characterized by progressive cognitive decline and memory loss.…”

Exploring the synthesis, structure, spectroscopy and biological activities of novel 4-benzylidene-1-(2-(2,4-dichloro phenyl)acetyl) thiosemicarbazide derivatives: An integrated experimental and theoretical investigation

“…Numerous investigations have shown the uses of Schiff's base-containing thiosemicarbazones in the pharmaceutical industry and medicinal chemistry ( Siddiqui et al, 2019 ). Thiosemicarbazones are versatile and powerful medicines due to their biological versatility as anti-tumor (compound a) ( Altıntop et al, 2016b ), anti-malarial (compound b) ( Khanye et al, 2010 ), anti-cancer (compound c) ( Kaplancıklı et al, 2016 ), anti-bacterial (compound d) ( Zhang et al, 2015 ), anti-fungal (compound e) ( Altıntop et al, 2016a ), urease (compound f) ( Hameed et al, 2015 ), cholinesterase (compound g) ( Khan et al, 2023 ), and α-glucosidase (compound h) ( Rahim et al, 2020 ) ( Fig. 1 ).…”