Natural Alkaloid Arecoline-Derived Amino Acid Derivatives: Design, Synthesis, and Evaluation of Their Antifungal Activity in an Agricultural Context

A novel series of arecoline derivatives featuring amino acid moieties and 2-aminopyridine scaffolds was designed, synthesized, and assessed against seven phytopathogens. Compound E15 emerged as the most potent derivative, exhibiting an EC₅₀ of 10.2 μg/mL against Botryosphaeria theobromae, representing an approximately 50-fold improvement over the parent compound, arecoline. Mechanistic investigations revealed that E15 disrupted hypha cell wall integrity, as evidenced by ultrastructural damage, hypha rupture, and subcellular disorganization. Transcriptomic profiling further confirmed its significant suppression of chitin biosynthesis pathways, while molecular docking validated strong interactions with chitin synthase. These findings position amino acid-pyridine hybridized arecoline derivatives as promising eco-friendly antifungals targeted at chitin metabolism.