3-Hydroxytyrosol as a Phenolic Cholinesterase Inhibitor with Antiamnesic Activity: A Multi–Methodological Study of Selected Plant Phenolics

Tugba Uçar Akyürek¹Fatma Sezer Senol Deniz¹Ipek Suntar¹Gokcen Eren¹Onur Kenan Ulutaş¹ILKAY ERDOGAN ORHAN^2*

• ¹Gazi Universitesi Eczacilik Fakultesi, Ankara, Türkiye
• ²Lokman Hekim University, Ankara, Türkiye

Context: Plant phenolics are increasingly being investigated for their diverse biological activities, including their neuroprotective effects relevant to conditions like Alzheimer's disease. Objective: The neurobiological potential of 37 plant phenolics was screened through a multi–faceted approach encompassing in vitro enzyme inhibition and antioxidant assays, in vivo antiamnesic evaluation, and in silico molecular docking and toxicity predictions. Materials and methods: The compounds were tested using microtiter assay for their cholinesterase (ChE) inhibition, metal–chelation activity, copper–reducing antioxidant capacity (CUPRAC), and ferric– reducing antioxidant power (FRAP) assays. Additionally, in silico ADME, pharmacokinetic, and toxicokinetic profiles of the compounds were predicted using computational platforms. Results: Several compounds exhibited significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Quercetin was found to be the most active inhibitor, with an IC50 of 1.22 ± 0.79 mM against AChE and 2.51 ± 0.04 mM against BChE. Other compounds, including caffeic acid (IC50: 3.51 ± 0.62 mM), apigenin (IC50: 3.52 ± 0.08 mM), and taxifolin (IC50: 7.18 ± 2.05 mM), were also able to inhibit AChE. Afterward, oleuropein, rosmarinic acid, gallic acid, EGCG, and 3–hydroxytyrosol were further investigated for their antiamnesic activity using a passive avoidance test in scopolamine-induced mice. Our data showed that the mentioned compounds were effective considering the latency time of the mice and the highest antiamnesic effect was shown by 3–hydroxytyrosol. The dual inhibitory compounds were then subjected to molecular docking experiments with ChEs. In silico toxicity of 3 compounds was assessed through PASS and SwissADME prediction programs. Discussion and conclusion: Our data provides compelling evidence for the neuroprotective potential of several plant phenolics. Notably, 3–hydroxytyrosol as an ChE inhibitor was identified for the first time with significant in vivo antiamnesic activity, warranting further investigation.