Autori: Ana-Marija Lulić, Lucija Marcelić, Alma Ramić, Andreja Radman Kastelic, Antonio Zandona, Nikola Maraković, Ines Primožič, Maja Katalinić
Sažetak rada
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 –CH3 or -Br substituent, with a Ki of around 1.7–2.0 μM (meta-position) for AChE and 0.3–0.5 μM (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 a certain level of cytotoxicity within the range of 1.5–17 μM, further research is needed to explore this effect, and to validate or negate their potential for development into therapeutic agents.
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