Design and synthesis of thiazolyl hydrazide derivatives as potent antifungal agent

Abstract BACKGROUND Fungal pathogen causes a persistent threat to global agricultural productivity. Thiazole and hydrazide derivatives exhibit broad‐spectrum and potent antifungal activity, demonstrating significant potential as novel antifungal agents. RESULTS In this article, 45 thiazolyl hydrazide derivatives were designed and synthesized as potential succinate dehydrogenase (SDH) inhibitors. These compounds exhibited broad‐spectrum antifungal activity against seven pathogens, notably compounds A5 and A33 showed the most significant activity against Pythium aphanidermatu m and Sclerotinia sclerotiorum , and compound A37 with cyclopropyl and 3‐chloro‐2‐fluorophenyl substituents showed significant efficacy against Rhizoctonia cerealis (half‐maximal effective concentration (EC 50 = 0.49 mg L −1 ) and Alternaria alternata (EC 50 = 1.81 mg L −1 ), while maintaining a comparable protective effect (88.5%) to that of the reference fungicide bixafen. The structure–activity relationship has also been analyzed in detail. Preliminary mechanistic studies indicated that compound A37 disrupted the tricarboxylic acid (TCA) cycle through inhibiting SDH. Concurrently, the activities of superoxide dismutase (SOD) and catalase (CAT) were reduced, resulting in elevated reactive oxygen species (ROS) levels and malondialdehyde (MDA) accumulation, which will damage the integrity of fungi cells. Molecular docking and molecular dynamics simulation confirmed the binding affinity of compound A37 with SDH. The cytotoxicity experiments indicated that the thiazolyl hydrazide derivatives belong to the low‐toxicity compounds. CONCLUSION Bioactivity screening and antifungal mechanism suggested the potential of thiazolyl hydrazide derivatives as promising, eco‐friendly candidates for the development of novel antifungal agents. © 2026 Society of Chemical Industry.