Synthesis of usnic acid derivatives and Cu(II) complex, investigation of their biological activities, and theoretical calculations

In this study, 2,6-diacetyl-7,9-dihydroxy-8,9b-dimethyldibenzo[b,d]furan-1,3(2H,9bH)-dione, known as usnic acid (UA), a natural compound with antioxidant properties and metal chelation regions, was selected as a precursor molecule. Three original UA derivatives and one Cu(II) complex were synthesized as cholinesterase inhibitors and metal chelators. These derivatives contain amino groups, which are known as critical pharmacophores for cholinesterase inhibition. Within the scope of the study, the antioxidant, anticholinesterase, and metal chelation activities of the derivatives were evaluated. The obtained results demonstrated that derivatives 1–3 exhibit superior antioxidant activities. In terms of scavenging capacity, the A0.5 value for Cu(II) was measured as 72.52 µM, and the IC50 value for ABTS was 118.67 µM. Furthermore, derivatives 1–3 were found to be effective in cholinesterase inhibition, with the highest percentage values calculated as 32.63% for acetylcholinesterase (AChE) and 29.31% for butyrylcholinesterase (BuChE). These results were consistent with findings from quantum chemical calculations and molecular docking studies conducted with AChE and BuChE. Additionally, in vivo studies demonstrated that the newly synthesized tert-butyl(E)-(2-((1-(6-acetyl-7,9-dihydroxy-8,9b-dimethyl-1,3-dioxo-3,9b-dihydrodibenzo[b,d]furan-2(1H)-ylidene)ethyl)amino)ethyl)carbamate (1), which can chelate with Cu(II), alleviated learning and memory dysfunctions, as well as depressive behaviors, in experimental animals with Alzheimer's induced by Cu(II) administration. It was also shown that the Cu(II)-induced Alzheimer model exhibited significant toxic effects on the liver and kidneys, whereas the therapeutic potential of compound 1 mitigated these effects.