Quercetin is a polyphenolic flavonoid compound with a proven wide range of biological activities including neuroprotective effects in neuronal injury/neurodegenerative disease models which is related with its high antioxidant properties. However, due to its low water-solubility, poor bioavailability, rapid clearance, instability, and inability to cross the blood–brain barrier (BBB) its potential application for treatment of central nervous system (CNS) disease is limited. Tetrahydroisoquinoline (THIQ) scaffold appears in many drugs’ structures applied in diverse medical applications. Recent research demonstrated their promising role in neuroprotection and in combating Alzheimer's disease. Specifically, their ability to inhibit acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) at micromolar concentrations could be linked to their anti-Alzheimer effects [1]. By combining these two classes of compounds we modified quercetin at its position 8 (resorcinol ring) with 6,7-dimethoxy-tetrahydroisoquinoline through Mannich reaction of quercetin with iminium ion formed from formaldehyde and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines structure. Newly obtained compound (Scheme 1) displayed higher lipophilicity than quercetin based on Swissadme prediction tool. the log P value is increased from -0.64 to 0.01 providing higher probability to cross BBB. Additionally, we tested the potentials of inhibition of AChE and BuChE of newly obtained compound and compared them with inhibition potentials of constituents. The obtained results pointed out that introduction of THIQ moiety into quercetin structure increases selectivity of new compound toward BuChE more than 100 times compared to AChE and slightly increases IC50 value for inhibition of BuChE.Scheme 1. The structure of synthesized compound.Bondžić et al. Int. J. Mol. Sci. 2024, 25, 1033.