Structure guided development of phenoxyethanol based N-aryloxyethyl heterocycles for the control of Phytophthora...

Late blight caused by the oomycete Phytophthora infestans remains one of the most devastating diseases threatening global potato and tomato production. Overuse of a narrow range of fungicides has sped up resistance, making it urgent to develop new agents that work differently and are safer.

In this study, a series of N-aryloxyethyl heterocycles were rationally designed by integrating the aryloxyethyl scaffold of phenoxyethanol with bioactive heterocyclic frameworks. Among the 40 synthesized derivatives, compound 8c exhibited the highest anti-oomycete activity against P. infestans, with an EC₅₀ value of 1.67 mg L^-1. In potted tomato assays, 8c provided over 90% protective and curative efficacy at 50 mg L^-1, comparable to carbendazim and slightly lower than cyazofamid. Untargeted metabolomic analysis revealed pronounced perturbations in tricarboxylic acid (TCA) cycle flux and amino acid biosynthesis, highlighting mitochondrial energy metabolism, with SDH-associated processes emerging as a sensitive metabolic node affected by 8c treatment. This finding was supported by enzymatic assays showing reduced SDH activity. However, the metabolic profile indicates a systemic bioenergetic collapse rather than simple enzyme inhibition. This suggests 8c likely disrupts mitochondrial membrane integrity, leading to an oxidative cascade marked by surging malondialdehyde (MDA) levels and compromised antioxidant defenses. Crucially, acute toxicity assays further indicated a favorable safety profile toward representative non-target organisms, including silkworms, zebrafish, and earthworms.

Collectively, these results identify compound 8c as a promising anti-oomycete lead that combines high efficacy, multi-level metabolic disruption, and encouraging safety characteristics for late blight management. © 2026 Society of Chemical Industry.