Selenocyanate Derivatives as Acetylcholinesterase Inhibitors: Potential Therapeutic Agents for Alzheimer’s Disease

Acetylcholinesterase (AChE) plays a key role in the pathophysiology of Alzheimer’s disease (AD) by promoting excessive hydrolysis of acetylcholine, leading to a marked cholinergic deficit. This increased enzymatic activity is directly linked to cognitive decline in AD, making AChE inhibition a cornerstone of current symptomatic treatment strategies [1]. In this context, organocalcogen compounds, particularly selenium derivatives, have gained attention due to their redox, antioxidant, and enzyme-modulating properties, as well as their versatility in coordinating with biomolecules [2,3]. In this study, the synthesis of two distinct classes of SeCN-containing derivatives, alkyl and aryl, was performed. The alkyl derivatives were obtained via established procedures involving bimolecular nucleophilic substitution reactions. In contrast, the aryl derivatives were synthesized through aromatic nucleophilic substitution, initiated by diazonium salt formation. As a result, a series of five compounds was successfully prepared and subsequently subjected to AChE inhibition assays in vitro using samples of mouse brains. Biological activity was assessed through a colorimetric assay using acetylthiocholine as substrate. Analysis of Variance (ANOVA) revealed a significant difference among groups [F_(26,52) = 34.97; p<0.0001]. Aromatic derivatives showed inhibitory activity from 15 µM, while aliphatic analogues were active from 10 µM. Rivastigmine (200 µM, a clinical AChE inhibitor) was used as positive control. The results demonstrate that selenocyanates present relevant inhibitory activity against cerebral AChE in vitro and stand out as promising candidates for the development of novel therapeutic approaches for AD.