Metabolomic and cheminformatic study of Sida hyssopifolia: A first record of potential multi-target antidiabetic compounds and chemotaxonomic comparison with Sida glabra and Sida rhombifolia

Abstract

The Mexican cloud forest harbors an exceptional diversity of vascular plants, most of which remain unexplored. Sida hyssopifolia C.Presl (Malvaceae) is reported for the first time in this ecosystem and was chemically characterized in this study. S. hyssopifolia methanolic extract showed in vitro inhibitory activity to α-amylase (αA, IC₅₀ = 0.02 mg/mL), α-glucosidase (αG, IC₅₀ < 1 × 10⁻⁶ mg/mL), and dipeptidyl peptidase-IV (DPP-IV, IC₅₀ = 0.92 mg/mL), and low acute toxicity in the Artemia salina test (LC₅₀ = 1.33 mg/mL). Using UPLC-MS/MS-based untargeted metabolomics, 550 metabolites were putatively annotated (MSI-levels 2–4). Paired comparisons between S. hyssopifolia vs. S. glabra and S. hyssopifolia vs. S. rhombifolia allowed the identification of 54 metabolites as exclusively accumulated in S. hyssopifolia (fold change ≥2; P ≤ 0.05). In addition, 18 metabolites were determined by OPLS-DA as the most important compounds in S. hyssopifolia compared to the related species (VIP-scores >1). The Bemis-Murcko scaffold analysis revealed potential enrichment in flavonoid glycosides and triterpene-related metabolites. Additionally, by UPLC-MS/MS-based targeted metabolomics it was confirmed the differential accumulation of 19 phenolic compounds (MSI-level 1). Furthermore, 13 accumulated compounds of S. hyssopifolia (MSI-levels 1–2, fold change ≥2, P ≤ 0.05) stood out since have been reported as αA, αG, and/or DPP-IV in vitro inhibitors. Integration of metabolomics and cheminformatics suggested S. hyssopifolia as a potential source of multi-target antidiabetic natural products. These findings provide insights into its chemotaxonomic character and underscore the significance of the Mexican cloud forest as a potential source of biologically active plants.