Rational design and discovery of novel hydrazide derivatives as potent succinate dehydrogenase inhibitors inspired by natural d/l‐camphor

Abstract BACKGROUND Succinate dehydrogenase inhibitors (SDHIs) have rapidly become one of the fastest‐growing categories of fungicides used against plant pathogenic fungi. Recent research advancements have emphasized that structural modifications of SDHIs using naturally sourced scaffolds represent an innovative strategy for developing new, highly effective, broad‐spectrum fungicides. A novel series of d/l ‐camphorhydrazide derivatives potentially targeting fungal succinate dehydrogenase (SDH) were designed, synthesized and evaluated for their antifungal effects against Rhizoctonia solani , Fusarium graminearum , Valsa mali and Botrytis cinerea . RESULTS Amongst them, compounds A1‐7 ( d ‐camphor) and A2‐7 ( l ‐camphor) displayed excellent in vitro activity against R. solani with median effective concentration (EC 50 ) values of 0.38 and 0.48 μg mL −1 , which were obviously superior to that of boscalid (0.87 μg mL −1 ). A2‐5 ( l ‐camphor, EC 50 = 3.27 μg mL −1 ) exhibited good activity against V. mali . A2‐7 (2.13 μg mL − 1), A2‐21 (5.2 μg mL −1 ) and A1‐5 (5.15 μg mL −1 ) showed good antifungal activity against F. graminearum with EC 50 values below that of boscalid (5.85 μg mL −1 ). Preliminary mechanistic studies, using scanning and transmission electron microscopy, indicated that compound A1‐7 induced disordered entanglement of hyphae, shrinkage of hyphal surfaces, and vacuole swelling and rupture, which disrupted normal hyphal growth. Additionally, compound A1‐7 induced the production and accumulation of reactive oxygen species, disrupted mitochondrial membrane potential, and effectively inhibited the germination and formation of sclerotia in R. solani . Moreover, the molecular docking results and SDH enzyme assays yielded promising outcomes. CONCLUSION In this study, the designed and optimized compounds A1‐7 and A2‐7 emerged as promising candidates for SDH‐targeting fungicides, demonstrating strong antifungal activity. These compounds hold potential as new antifungal agents for further research. © 2024 Society of Chemical Industry.