Novel 1,2,3,4-tetrahydroisoquinoline-based Schiff bases as laccase inhibitors: Synthesis and biological activity, 3D-QSAR, and molecular docking studies

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Laccase is considered a potential target in the field of agricultural fungicides. To promote the discovery and development of compounds with laccase inhibitory activity, herein, taking reported laccase inhibitor 4-chlorocinnamaldehyde thiosemicarbazide (PMDD-5Y) as the lead compound, two series of 29 novel Schiff-base compounds were designed and synthesized by introducing natural structural unit 1,2,3,4-tetrahydroisoquinoline for the first time. All the synthesized compounds had good antifungal activities against several phytopathogenic fungi in vitro. Among them, compound 4k exhibited prominent biological activities against Valsa mali (EC50 = 5.37 µg/mL), Rhizoctonia solani (EC50 = 3.51 µg/mL), and laccase (IC50 = 0.047 mmol/L), and, thus, could be a promising candidate for a novel chemical fungicide targeting laccase. Furthermore, the structure-activity relationship of the compounds were studied using three-dimensional quantitative structure–activity relationships, molecular docking, and density functional theory calculations. The experimental results preliminarily suggested that the active hydrogen on the nitrogen atom, which acts as a positively charged region, can form key interactions with the laccase target. This may be a key factor in influencing the biological activity.