Structure-Activity Relationship of Novel Phenolic-Branched Amides Reveals Potent, Isolate-specific Antifungal Activity and Morphological Disruption of Cacao Fungal Pathogens

Fungal pathogens, including Colletotrichum gloeosporioides and Pestalotiopsis spp., are significant threats to global cacao production. Understanding their response to novel antifungal compounds is crucial for developing new and effective plant protection strategies. To establish a clear structure-activity relationship (SAR), this study investigated the in vitro effects of four novel phenolic-branched fatty acids and their corresponding ethylenediamine-carrying amides on three cacao pathogen isolates (one Pestalotiopsis sp. and two C. gloeosporioides). A high degree of isolate-specific susceptibility was observed, and the chemical structure of the compounds was found to be the key determinant of antifungal efficacy. A phenol-branched soy oil-derived fatty amide (PhSOAM) proved most potent, significantly inhibiting the growth of Pestalotiopsis sp. and one C. gloeosporioides isolate, while the second C. gloeosporioides isolate was completely resistant. The conversion of the carboxylic acid to its amide derivative was critical for this enhanced activity. Notably, PhSOAM uniquely altered fungal colony morphology by increasing the length-to-width ratio, suggesting a mechanism of action involving the disruption of polarized growth. Multivariate analyses and machine learning models, developed to predict pathogen growth (R² up to 0.94), identified the specific compound structure and pathogen isolate as the most critical factors determining the interaction outcome. This work not only identifies PhSOAM as a promising lead compound for agricultural applications but also establishes a powerful analytical framework, combining morphological profiling with predictive modeling, to gain deeper insights into the complex, isolate-specific nature of fungal-antifungal interactions.