Laccase‐Catalyzed Dimerization of Honokiol and Magnolol for Multitarget Metabolic Enzyme Inhibitors

Laccases are biocatalysts with a high potential for developing green procedures to achieve new compounds. This study employed laccases in buffer solution to synthesize dimeric neolignans from honokiol and magnolol. Four laccases (LTV, POXA1b, EV3, and EV4) were first screened for honokiol dimerization in the presence of the mediator, with the variant EV4 achieving with the highest yield and in a shorter timeframe the natural houpulin A and B. Reaction conditions were optimized using a mathematical model to maximize the recovery of the desired products, achieving up to 3.42% yield. Interestingly, the optimized conditions also afforded the synthesis of other dimeric compounds, a magnolol dimer and a mixed honokiol–magnolol dimer with comparable yields. In silico studies investigated the substrate's compatibility with the EV4 binding site, highlighting the noncovalent interactions that enhance the stability of the radical formation, thus supporting the production of the obtained products. The four dimeric compounds were studied as metabolic enzyme inhibitors (lipase, α-amylase, and α-glucosidase) by in vitro and in silico experiments. The dimers exhibited more potent inhibitory activity than honokiol and magnolol, with houpulin B showing the strongest inhibition toward all tested enzymes.