Design, synthesis, and antiviral activity of novel piperidine‐containing pyrazoleamide derivatives

Abstract BACKGROUND Plant viruses such as tobacco mosaic virus (TMV) pose a serious threat to global crop production, making the development of highly effective antiviral agents an urgent task in agricultural plant protection. RESULTS Three series of pyrazoleamide‐piperidine derivatives were designed and synthesized, and their antiviral activities against TMV were evaluated. Compounds H9 and X18 exhibited protective half‐maximal effective concentration (EC 50 ) values of 69.52 mg L −1 and 82.27 mg L −1 , respectively, while the EC 50 for commercial antiviral agent ningnanmycin is 81.73 mg L −1 . TMV‐GFP imaging revealed that compound H9 pretreatment more effectively delayed systemic TMV infection. The mechanism of action study indicated that compounds H9 and X18 enhanced the activity of defense enzymes such as superoxide dismutase (SOD), peroxidase (POD), polyphenol oxidase (PPO), and phenylalanine ammonia‐lyase (PAL). Additionally, they mitigated chlorophyll degradation and promoted chlorophyll production. Treatment with compound H9 up‐regulated genes such as PR1 , activating systemic acquired resistance in plants and enhancing TMV resistance. Concurrently, treatment with compound X18 up‐regulated genes including CYP73A , CYP98A , and PAL , activating the phenylpropanoid pathway to promote lignin synthesis and enhance the cell barrier, thereby inhibiting TMV infection. These reverse transcription quantitative polymerase chain reaction (RT‐qPCR) results were consistent with transcriptomic data. CONCLUSION Compounds H9 and X18 enhanced TMV resistance through distinct mechanisms, informing the development of novel green antiviral agents. © 2026 Society of Chemical Industry.