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.

漆酶被认为是农业杀菌剂领域的一个潜在目标。为促进具有漆酶抑制活性的化合物的发现和开发，本文以报道的漆酶抑制剂4-氯肉桂醛氨基硫脲(PMDD-5Y)为先导化合物，通过引入天然结构设计合成了两个系列的29个新型席夫碱化合物。单元1,2,3,4-四氢异喹啉为首次。所有合成的化合物在体外对几种植物病原真菌均具有良好的抗真菌活性。其中化合物4k对Valsa mali (EC ₅₀  = 5.37 µg/mL)、立枯丝核菌( Rhizoctonia solani (EC ₅₀ = 3.51 µg/mL) 和漆酶 (IC ₅₀  = 0.047 mmol/L)，因此，可能成为靶向漆酶的新型化学杀菌剂的有前途的候选者。此外，利用三维定量构效关系、分子对接和密度泛函理论计算研究了化合物的构效关系。实验结果初步表明，作为带正电区域的氮原子上的活性氢可以与漆酶靶点形成关键相互作用。这可能是影响生物活性的关键因素。