Diterpenes and New Antifungal Epimers Derived From Grindelia puberula Hook & Arn. In Vitro and In Silico Studies

Two new labdane diterpenes, (4S,5R,10S,13S)-19-acetoxy-7-oxo-labd-8(9)-en-15-oic acid-15-methyl ester (1) and (4R,5R,10S,13S)-19-acetoxy-7-oxo-labd-8(9)-en-15-oic acid-15-methyl ester (2), along with two methyl ester derivatives of the known acid compounds, (4R,5S,9S,10R,13S)-ent-7-labden-17-acetoxy-18-hydroxy-15-oic acid (3), and (3R,5S,9S,10S,13S)-ent-7-labden-17-acetoxy-3-α-hydroxy-15-oic acid (4), were obtained from Grindelia puberula Hook & Arn, collected in northern Argentina. Their structures and absolute configurations were elucidated based on one- and two-dimensional nuclear magnetic resonance spectroscopy, mass spectrometry, and circular dichroism analysis. The CHCl₃ sub-extract obtained from the aerial parts of this species, along with the pure compounds, were evaluated for antifungal activity against Botrytis cinerea, a widespread necrotrophic fungal pathogen responsible for significant economic losses worldwide. Among the tested compounds, 2 (IC₅₀ = 27.7 ± 3.8 µg/mL) exhibited the highest antifungal activity, demonstrating greater efficacy compared to its C-4 epimer. Furthermore, an in silico structure-activity relationship study was conducted. Molecular docking simulations revealed that compound 2 displayed the highest binding affinity to the B. cinerea cytochrome b complex (-9.62 kcal/mol), a key target in antifungal therapy.