Amino acid vectorization of salicylic acid enables efficient activation of NPR1-dependent defense without phytotoxicity.

Addressing global food security under rapid population growth and climate change requires sustainable strategies to protect crops from pathogens while reducing reliance on agrochemicals. Salicylic acid (SA), a key phytohormone in plant defense, is a promising natural elicitor for crop protection. However, its rapid metabolism and phytotoxicity restrict practical use. To overcome these limitations, we developed SA-amino acid conjugates designed to improve protective efficacy of SA while minimizing its toxicity. Six SA-amino acid conjugates were synthesized through optimized multistep routes using either diaminocarboxylic acids or l-glutamic acid with various linkers. Their defense-inducing activity was evaluated in Arabidopsis thaliana (L.) Heynh. (PR1::GUS reporter line) and in disease-resistance assays against Pseudomonas syringae pv. tomato (Okabe) Young et al. and Pseudomonas syringae pv. maculicola (McCulloch) Young et al. Conjugates 3a and 7a efficiently activated PR1 expression and conferred NPR1-dependent resistance comparable to free SA, while preventing SA-associated phytotoxicity. The other conjugates showed lower or no activity, revealing a clear structure-activity relationship. This study highlights SA-amino acid conjugates as effective, non-phytotoxic inducers of plant immunity. Structure-activity analyses indicate that both the nature of the SA-amino acid linkage and the properties of the amino acid side chain modulate biological activity, induction kinetics, and toxicity. Conjugates 3a and 7a combine strong protective efficacy with the absence of SA-associated phytotoxicity, supporting amino acid vectorization as an effective approach for safer and controlled SA delivery and the rational design of next-generation defense stimulators for sustainable crop protection. © 2026 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.