This work reports the design and preparation of 18 novel phenylpyrazole derivatives containing 1,3,4-oxadiazole or thiadiazole groups (F1-F18), followed by an assessment of their antifungal potential against eight phytopathogenic fungi. Most compounds displayed notable efficacy, particularly against Valsa mali and Sclerotinia sclerotiorum. Notably, compound F15 demonstrated superior in vitro activities with EC50 values of 1.89 μg/mL (V. mali) and 0.78 μg/mL (S. sclerotiorum), outperforming boscalid against V. mali. In vivo trials revealed that F15 conferred 90.9 % protective and 60.6 % curative efficacy on S. sclerotiorum-infected oilseed rape leaves, without phytotoxicity. Mechanistic studies using CLSM, SEM, and PI staining indicated that F15 compromises hyphal membrane integrity, while DCFH-DA assay confirmed ROS accumulation leading to cell death. Density functional theory (DFT) calculations revealed that F15 possesses a narrow energy gap (ΔEHOMO-LUMO = 0.1027 eV) and distinctive electrostatic potential properties conducive to bioactivity. Additionally, compound F15 showed favorable ADMET properties and low acute oral toxicity to Apis mellifera ligustica (LC50 = 653.1 μg/mL). These findings underscore the potential of F15 as a promising eco-friendly antifungal agent for agricultural applications.
