Cristiani Folharini Bortolatto

A highly efficient and selective protocol for the halogenation of the C─H bond of 4‐aminocoumarin derivatives is reported. This shows that the use of trihaloisocyanuric acids in the synthesis of aminocoumarin derivatives consists of obtaining pharmacologically important compounds using new strategies and transformations. The proposed method has a broad substrate scope and uses ethyl acetate as the solvent. The reaction scope evaluation of 4‐aminocoumarins with different structural characteristics showed that the reaction tolerates electron‐withdrawing groups (compounds 3d–f and 8c–e ) and electron‐donating groups (compounds 3b‐c , 3g , 5 , 7 , and 8b ). A sterically hindered group attached to the nitrogen at C4 was also tolerated in the bromination reaction (compound 3h ), as well as an alkyl group (compound 7 ) and even the absence of a substituent on the nitrogen (compound 5 ). Molecular docking results show that, among the compounds tested, compound 3h stands out. Its predicted interactions with acetylcholinesterase (AChE), monoamine oxidase B (MAO‐B), β‐secretase enzyme (BACE), and N‐methyl‐D‐aspartate receptors (NMDAR) suggest a promising profile for inhibiting these neurochemical enzymes and antagonizing glutamatergic NMDAR, potentially contributing to therapeutic strategies for neurodegenerative diseases such as Alzheimer's disease.

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.