Chemical profiling, biological evaluation, and QSAR-informed metabolite prioritization of Hypericum ekerii: a first report on antioxidant, enzyme inhibitory, and cytotoxic activities

Hypericum ekerii Yüce and Aytaç, first described in 2017, remains poorly characterized in terms of its phytochemical composition and biological properties. This study investigated aerial-part extracts of H. ekerii prepared with ethyl acetate, acetone, 70% acetone–water, and water. The hydroacetone extract showed the highest total phenolic and flavonoid contents. LC/MS analysis enabled the annotation of 99 constituents, including phenolic acids, flavonoids, xanthones, anthraquinones, and acylphloroglucinols. The hydroacetone extract exhibited the strongest radical-scavenging and reducing activities, whereas acetone and ethyl acetate extracts showed the highest metal-chelating capacity. In enzyme assays, hydroacetone was the most active extract against acetylcholinesterase, tyrosinase, and hCA II, while ethyl acetate showed greater inhibition of butyrylcholinesterase and hCA I. The aqueous extract was the most active against α-glucosidase, and hydroacetone and ethyl acetate showed comparable α-amylase inhibition. Cytotoxicity remained limited overall; the lowest IC₅₀ value was observed for the ethyl acetate extract against HCT-116 cells (95.09 µg mL⁻¹), with weak selectivity (SI = 1.2). A QSAR-informed prioritization framework identified myricetin as the leading cross-layer candidate, p-coumaric acid as a target-specific priority metabolite, and ellagic acid, quercetin, and caffeic acid as antioxidant-priority candidates. Molecular docking supported favorable binding profiles for selected metabolites, while molecular dynamics simulations were used to assess the stability of representative complexes. Overall, H. ekerii appears to be a chemically diverse species with notable antioxidant and enzyme-inhibitory potential, providing a focused basis for future compound-level validation.