Synthesis of Novel Chromene Derivatives Bearing Hydrazide/Thiazol/Oxazol/Oxime Moieties as Potential Antifungal Agents

Four series of novel hydrazide/thiazol/oxazol/oxime ester hybrids of chromene derivatives were designed and synthesized to explore natural-product-based fungicide candidates. Preliminary antifungal activity assay results demonstrated that hydrazide-chromene and thiazol-chromene derivatives exhibited excellent and broad-spectrum inhibitory activity against ten phytopathogenic fungi. Among them, six compounds 4b, 4c, 4d, 4e, 4h, and 4l displayed the most remarkable antifungal effects. Notably, compounds 4e and 4l showed comparable protective and curative effects with chlorothalonil against potatoes and cherry tomatoes infected by Fusarium solani and Botrytis cinerea, respectively. Meanwhile, compound 4e also exerted potential protective and curative effects against rice and pepper leaves infected by Pyricularia oryzae and Phytophthora capsici, respectively. Additionally, a preliminary antifungal mechanism study revealed that compound 4e could significantly inhibit the germination of spores and promote increased mycelium permeability and content leakage by disrupting the fungal membrane structure. The in vitro cytotoxicity results indicated that almost all of the hydrazide-chromene derivatives possessed relatively low cytotoxicity. These findings provide the foundation for the application of chromene-based derivatives as novel fungicide candidates.