article · Molecules
A series of new triazole-based thiosemicarbazone derivatives, designated 6a to 6u, was synthesised and structurally characterised using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The compounds were evaluated in laboratory tests for their inhibitory activity against acetylcholinesterase and butyrylcholinesterase enzymes. With the exception of two inactive analogues, the derivatives showed moderate to good inhibition, with IC50 values ranging between 0.10 and 12.20 micromolar for acetylcholinesterase and between 0.20 and 14.10 micromolar for butyrylcholinesterase. Derivatives 6i and 6b proved to be the most potent dual inhibitors of both targeted enzymes across the series. Structure-activity relationship analyses established how the positions and electronic properties of substituents on the phenyl rings affected potency, while computational molecular docking detailed the binding interactions of the most active compounds within the enzyme active sites.
Therapeutic strategies for Alzheimer's disease often involve inhibiting cholinesterase enzymes to preserve brain function. Developing synthetic compounds that target both acetylcholinesterase and butyrylcholinesterase can offer valuable lead structures for pharmaceutical exploration. This work supplies chemical data and binding models that help researchers design more targeted dual-action inhibitors for neurodegenerative disease studies.
The identified derivatives represent early-stage lead candidates for medicinal chemists and pharmaceutical developers working on treatments for Alzheimer's disease. Given that the evidence is strictly limited to in vitro enzymatic assays and computational modelling, the compounds remain far from real-world application. Extensive preclinical development, including toxicity evaluations, cellular models, and in vivo pharmacokinetic studies, would be required before these compounds could advance toward commercial drug development.
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Triazole-based thiosemicarbazone derivatives (<b>6a-u</b>) were synthesized then characterized by spectroscopic techniques, such as 1HNMR and 13CNMR and HRMS (ESI). Newly synthesized derivatives were screened in vitro for inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. All derivatives (except <b>6c</b> and <b>6d</b>, which were found to be completely inactive) demonstrated moderate to good inhibitory effects ranging from 0.10 ± 0.050 to 12.20 ± 0.30 µM (for AChE) and 0.20 ± 0.10 to 14.10 ± 0.40 µM (for BuChE). The analogue <b>6i</b> (IC<sub>50</sub> = 0.10 ± 0.050 for AChE and IC<sub>50</sub> = 0.20 ± 0.050 µM for BuChE), which had di-substitutions (2-nitro, 3-hydroxy groups) at ring B and tri-substitutions (2-nitro, 4,5-dichloro groups) at ring C, and analogue <b>6b</b> (IC<sub>50</sub> = 0.20 ± 0.10 µM for AChE and IC<sub>50</sub> = 0.30 ± 0.10 µM for BuChE), which had di-Cl at 4,5, -NO<sub>2</sub> groups at 2-position of phenyl ring B and hydroxy group at ortho-position of phenyl ring C, emerged as the most potent inhibitors of both targeted enzymes (AChE and BuChE) among the current series. A structure-activity relationship (SAR) was developed based on nature, position, number, electron donating/withdrawing effects of substitution/s on phenyl rings. Molecular docking studies were used to describe binding interactions of the most active inhibitors with active sites of AChE and BuChE.
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DOI: 10.3390/molecules28010021
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