Lulic_2025_Chem.Biol.Interact__111567

In this study, we investigated the inhibitory activity of novel dodecylaminoquinuclidines (QAs) on neurotransmitter-hydrolyzing enzymes, specifically acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Following our previous findings, we modified the structure of a lead compound to develop more potent modulators of cholinesterase activity. The search for such inhibitors remains a key focus in the therapeutic management of organophosphate poisoning and various neurological disorders. For the design, we retained the aliphatic side linker and introduced various benzyl-based substituents to the quinuclidinium core, resulting in a set of 11 new compounds. All of these derivatives exhibited reversible inhibition of cholinesterase within the micromolar concentration range. The most significant factor affecting inhibition was the positional change of a specific group on the benzene ring, shifting from the meta to the para position. Specifically, analogues with groups in the meta position showed a stronger inhibition of AChE, whereas the para position was more effective for BChE. The most potent inhibitor featured a -CH(3) or -Br substituent, with a K(i) of around 1.7-2.0 microM (meta-position) for AChE and 0.3-0.5 microM (para-position) for BChE. Additionally, we assessed the cytotoxicity of these compounds on human neuronal SH-SY5Y cells, as their intended target in the body. As all tested quinuclidine derivatives demonstrated certain level of cytotoxicity within the range of 1.5-17 microM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.