Enhanced Bioactivity of Quercetin-Tetrahydroisoquinoline Derivatives: Effect on Lipophilicity, Enzymes Inhibition, Antioxidant Potential, and Cytotoxicity.

Quercetin, a well-known flavonoid with significant medicinal potential, was derivatized at the C8 position with a tetrahydroisoquinoline (THIQ) moiety, and physicochemical and pharmacological properties, inhibition potential, antioxidant activity, and cytotoxicity of new compounds were evaluated. Physicochemical and pharmacological properties, including lipophilicity, membrane permeability, and P-glycoprotein substrate affinity, were assessed theoretically using the SwissADME software. The metal-chelating ability of the new compounds was evaluated on metal ions Fe, Zn, and Cu, whose homeostasis disruption is linked to the development of Alzheimer's disease. Inhibition potential was tested on the cholinergic enzymes acetylcholinesterase and butyrylcholinesterase, as well as Na, K-ATPase, an enzyme commonly overexpressed in tumours. Antioxidant potential was assessed using the DPPH assay. Cytotoxicity studies were conducted on healthy MRC-5 cells and three cancer cell lines: HeLa, MDA-231, and MDA-468. The results indicated that derivatization of quercetin with THIQ yielded compounds with lower toxicity, preserved chelating ability, improved antioxidant potential, increased selectivity toward the cholinergic enzyme butyrylcholinesterase, and enhanced inhibition potential toward Na, K-ATPase and butyrylcholinesterase compared to quercetin alone. Therefore, the synthesized derivatives represent compounds with an improved profile and could be promising candidates for further optimization in developing drugs for neurodegenerative and cancer diseases.