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

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 biolog-ical activities against Valsa mali (EC50 = 5.37 mu g/mL), Rhizoctonia solani (EC50 = 3.51 mu g/mL), and lac -case (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 ni-trogen 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. (c) 2023 Published by Elsevier B.V.