Current topics in medicinal chemistry · 2026
Synthesis of New Coumarin-Based Selenotriazoles as Acetylcholinesterase Inhibitors for Cholinergic Dysfunction.
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V T Martins Cristal, Hall Tacia K, Goncalves Rodrigues da Cruz Analice, S Souza Acácio, B Ribeiro Ruan Carlos, C A Pinto Douglas, Cordeiro Pamella, Brüning Cesar Augusto, de C da Silva Fernando, Nascimento Vanessa, Folharini Bortolatto Cristiani, da S M Forezi Luana
Аннотация
INTRODUCTION: AChE inhibitors enhance cholinergic neurotransmission and are used to treat neurological disorders. This study synthesized novel coumarin-based selenotriazole compounds by combining coumarin, organoselenium, and 1,2,3-triazole moieties, given their antioxidant, neuroprotective, and enzyme-inhibitory effects, with the aim of achieving a synergistic pharmacological profile.
MATERIALS AND METHODS: They were initially evaluated via in silico molecular docking studies against AChE, using rivastigmine as a reference compound. The most promising molecules were subsequently subjected to in vitro screening to assess their inhibitory activity against AChE from the brains of female Swiss mice. Further investigations included detailed binding interaction analyses and in silico ADMET predictions.
RESULTS: Docking simulations showed the compounds had better binding affinities than rivastigmine. In vitro assays identified five potent AChE inhibitors (7b, 7h-j, 7l), with 7b and 7j as the top candidates. Docking revealed key interactions at the enzyme's catalytic site. ADMET predictions indicated good absorption, metabolism, moderate CNS permeability, and acceptable toxicity, though hepatotoxicity and hERG II inhibition remain concerns for future study.
DISCUSSION: The combination of coumarin, organoselenium, and triazole pharmacophores proved effective in modulating AChE activity, suggesting a synergistic effect among these structural units. 7b and 7j stood out in terms of both biological activity and predicted pharmacokinetic properties, establishing them as promising lead candidates for further development. Toxicological concerns highlight the importance of future structural optimization to minimize potential adverse effects.
CONCLUSION: Compounds 7b and 7j are promising AChE inhibitor lead compounds for treating cholinergic disorders like Alzheimer's disease. Further in vivo studies and optimization are needed.
MATERIALS AND METHODS: They were initially evaluated via in silico molecular docking studies against AChE, using rivastigmine as a reference compound. The most promising molecules were subsequently subjected to in vitro screening to assess their inhibitory activity against AChE from the brains of female Swiss mice. Further investigations included detailed binding interaction analyses and in silico ADMET predictions.
RESULTS: Docking simulations showed the compounds had better binding affinities than rivastigmine. In vitro assays identified five potent AChE inhibitors (7b, 7h-j, 7l), with 7b and 7j as the top candidates. Docking revealed key interactions at the enzyme's catalytic site. ADMET predictions indicated good absorption, metabolism, moderate CNS permeability, and acceptable toxicity, though hepatotoxicity and hERG II inhibition remain concerns for future study.
DISCUSSION: The combination of coumarin, organoselenium, and triazole pharmacophores proved effective in modulating AChE activity, suggesting a synergistic effect among these structural units. 7b and 7j stood out in terms of both biological activity and predicted pharmacokinetic properties, establishing them as promising lead candidates for further development. Toxicological concerns highlight the importance of future structural optimization to minimize potential adverse effects.
CONCLUSION: Compounds 7b and 7j are promising AChE inhibitor lead compounds for treating cholinergic disorders like Alzheimer's disease. Further in vivo studies and optimization are needed.