Utilization of natural product for developing promising sterol biosynthesis inhibitors: design, synthesis and antifungal evaluation of cyclic trialkylamine derivatives

To further discover novel natural product-based fungicide candidates, a series of novel kakuol-based trialkylamine derivatives were synthesized and structurally confirmed through NMR spectroscopy, and HRMS. Especially, the stereochemical structure of trialkylamine 3p was confirmed by using single crystal X-ray diffraction analysis. Antifungal bioassay showed that trialkylamine 3c exhibited significant in vitro Antifungal activity against the mycelium growth of Gaeumannomyces graminis with the EC₅₀ value of 30.6 μg/mL and trialkylamine 3n displayed the obvious in vitro Antifungal activity against Colletotrichum orbiculare with the EC₅₀ value of 34.1 μg/mL. Moreover, in vivo inhibitory activity on the cucumbers indicated that trialkylamine 3n exhibited favorable curative effect against C. orbiculare at 200 μg/mL with inhibition rate of 58.2%, clearly superior to that of hymexazol (45.5%). Preliminary exploration on the Antifungal mechanism of action on the cell membrane indicated that trialkylamine 3n treatment may increase the cellular contents release, resulting in damaging the permeability of the cell membrane. Further toxicity evaluation revealed that the aforementioned potent trialkylamine derivatives displayed relatively low to moderate cytotoxicity to normal LO2 cells for mammals. Overall, this work provides valuable strategy for developing kakuol-derived trialkylamine hybrids as potential Antifungal agrochemicals.