Abstract BACKGROUND Plant virus causes severe yield losses in cash crops such as pepper and tomatoes, and efficient antiviral agents remain an urgent demand in agricultural pest control. RESULTS Two series of pyrazoline acylhydrazone derivatives ( A‐1 ~ A‐18 and morpholine‐containing T‐1 ~ T‐27 ) were synthesized and evaluated for their anti‐tobacco mosaic virus (TMV) activity. Promisingly, the introduction of a morpholine ring in the T ‐series increased curative activity by 10–78%, and protective activity by 6–72%. DFT calculations indicated that compound T‐8 , which contains a morpholine structure, exhibited significant spatial separation between its HOMO and LUMO distributions compared to morpholine‐free compound A‐13 . This spatial separation favors the establishment of an intramolecular charge‐transfer channel, thus enhancing electron transfer efficiency during target binding. T‐19 demonstrated significantly curative and inactivation activities of 80.9 and 90.5%, respectively, which is superior or similar to that of commercialized Ningnanmycin (67.2 and 89.6%, respectively). The results of molecular docking, dynamic simulation, qRT‐PCR, microscale thermophoresis and transmission electron microscope revealed that T‐19 showed a strong affinity with TMV coat protein, resulting in a direct disruption of viral particles and inhibiting viral replication and systematic movement in host plant. CONCLUSION T ‐series with morpholine ring led to a substantial enhancement in antiviral potency compared to A ‐series, and the discovery of T‐19 provides an innovative design strategy for antiviral candidate. © 2026 Society of Chemical Industry.
Liao et al. (Sat,) studied this question.