Senkyunolide B exhibits broad‐spectrum antifungal activity against plant and human pathogenic fungi via inhibiting spore germination and destroying the mature biofilm.

BACKGROUND: Aspergillus infection seriously jeopardizes the health and safety of life of immunocompromised patients. The emergences of antifungal resistance highlight a demand to find new effective antifungal drugs. Angelica sinensis is a medicine–food herb and phthalides are its characteristic components. A few of the phthalides have been reported to display satisfactory antifungal activities against plant pathogenic fungi. However, the structure–activity relationships and antifungal action mechanism of phthalides remain to be further explored and elucidated. RESULTS: The antifungal activities of five natural phthalides and four artificial analogs were investigated, and their structure–activity relationships were preliminarily elucidated in the current study. The benzene ring moiety played an essential role in their antifungal activities; the oxygen‐containing substituents on the benzene ring obviously impacted their activities, the free hydroxyl was favorable to the activity. Typical phthalide senkyunolide B (SENB) exhibited broad antifungal activities against human and plant pathogenic fungi, especially, Aspergillus fumigatus. SENB affected the spore germination and hyphae growth of Aspergillus fumigatus via down‐regulating phosphatidylinositol‐PKC‐calcineurin axis and the expression of ENG genes. Moreover, SENB disturbed the oxidation–reduction process in Aspergillus fumigatus to destroy the mature biofilms. In vivo experiments indicated SENB significantly prolonged survival and decreased fungal burden in mouse model of invasive pulmonary aspergillosis. CONCLUSIONS: Phthalides could be considered as the valuable leads for the development of antifungal drug to cure plant and human disease. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]