Lichens as a Source of Nematocidal Compounds: Identification of Sphaerophorin and Divaricatic Acid Active against Caenorhabditis elegans

Abstract Increasing helminth drug resistance necessitates novel anthelmintic agents. Lichens, historically used to treat parasitic infections, represent a promising natural resource. This study evaluated eight lichen extracts and 17 metabolites against the model organism Caenorhabditis elegans (wild-type strain N2). Extracts of Hypogymnia physodes, Nephroma arcticum, and Stereocaulon grande showed significant efficacy, while Sphaerophorus fragilis and Ophioparma ventosa caused 100% nematode mortality on day 11 (at 25 and 100 μg/mL, respectively). Chemical workup of S. fragilis yielded squamatic acid, sphaerophorin, and its monocyclic degradation products. Among the tested compounds, the depside sphaerophorin exhibited the highest nematocidal activity (LC50 = 22.07 μM), followed by divaricatic acid (LC50 = 77.27 μM). Physodic acid (LC50 > 200 μM) and evernic acid showed moderate effects. Sphaerophorin and divaricatic acid demonstrated moderate to low selectivity, generally exhibiting lower cytotoxicity toward human CCD-18Co cells (CC50 values of 88.5 μM and 91.7 μM, respectively) than toward nematodes. Given a panel of 17 structurally related compounds, we conducted a structure–activity relationship (SAR) analysis to identify molecular patterns associated with observed nematocidal activity. The analysis suggested the importance of the intact depside structure together with the presence of aliphatic chains and a carboxylic group, as isolated monocyclic fragments lacked antinematode efficacy. This first report on the nematocidal activity of H. physodes, N. arcticum, S. grande, and S. fragilis extracts, alongside evernic acid, physodic acid, and sphaerophorin, against the model organism C. elegans identifies them as promising scaffolds that warrant further investigation against parasitic species.