Phytochemical Profiling of the Halophyte Suaeda vera and Antileishmanial Evaluation of Its Extracts and Selected Metabolites, with In Silico ADMET Analysis

Plant-derived secondary metabolites are a promising source of new anti-infective agents owing to their remarkable chemical diversity and broad spectrum of biological activities. Among them, halophytes are particularly promising because adaptation to saline environments promotes the accumulation of structurally diverse secondary metabolites. In the present study, organic extracts from four Tunisian halophytic species collected across different seasons were evaluated for their activity against Leishmania infantum axenic amastigotes, the etiological agent of visceral leishmaniasis in the Mediterranean Basin. Among the species tested, Suaeda vera was the only one to exhibit significant antileishmanial activity. Mass spectrometry-based phytochemical profiling of the bioactive extracts resulted in the putative annotation of 53 secondary metabolites and revealed qualitative differences in their annotated chemical composition among the seasonal samples. Three compounds putatively annotated in the active extracts—demethylzeylasteral, caffeic acid, and protocatechuic aldehyde—were subsequently evaluated individually using commercially available reference compounds and exhibited EC50 values of 0.20, 1.09, and 14.56 μM, respectively. Caffeic acid displayed the most favorable overall profile, combining potent antileishmanial activity with a high selectivity index (SI > 91.7) in mouse intestinal organoids. In vitro assays revealed that none of the three compounds inhibited trypanothione reductase-associated activity. Furthermore, in silico drug-likeness and ADMET analyses suggested that caffeic acid may have a comparatively favorable predicted pharmacokinetic and toxicity profile among the three compounds evaluated. Collectively, these findings highlight S. vera as a promising source of antileishmanial metabolites and establish caffeic acid as the most promising hit compound for further investigation.