Design, synthesis, and mechanism study of novel tetrahydroisoquinoline derivatives as antifungal agents

In screening for natural-derived fungicides, a series of 32 novel tetrahydroisoquinoline derivatives were designed and synthesized based on tetrahydroisoquinoline alkaloids. Their structures were verified by ¹H NMR, ¹³C NMR, HRMS, and single X-ray crystal diffraction analysis. Most of the target products exhibited medium to excellent antifungal activity against 6 phytopathogenic fungi in vitro at a concentration of 50 mg/L. Interestingly, compounds A13 and A25 with EC₅₀ values of 2.375 and 2.251 mg/L against A. alternate were similar to boscalid (EC₅₀ = 1.195 mg/L). The in vivo experiments revealed that A13 presented 51.61 and 70.97% protection activities against A. alternate at the dosage of 50 and 100 mg/L, respectively, which were equal to that of boscalid (64.52 and 77.42%). SDH enzyme assays and molecular docking studies indicated that compound A13 may act on SDH. In addition, the SEM analysis showed that compound A13 could strongly damage the mycelium morphology. These results revealed that A13 may be a promising lead compound for the development of natural-derived fungicides.

A series of novel tetrahydroisoquinoline derivatives A1–A32 were rationally designed and synthesized based on tetrahydroisoquinoline alkaloids.