## 2 Materials and Methods
### UHPLC-DAD-MS Instrument  
To identify the compounds in the extract fractions that showed greater biological activity, high-resolution UHPLC equipment coupled to a MS (Thermo Dionex Ultimate 3000 system with a DAD detector controlled by Chromeleon 7.2 software, linked with a Thermo Q-Exactive MS focus) was used. In the process, 5 mg of sample was dissolved in 2 mL of methanol, which was subsequently passed through a 200 \(\upmu\)m polytetrafluoroethylene (PTFE) filter before being injected into the equipment [26].  
LC Parameters and MS Parameters  
HPLC chromatography was performed using a HPLC Carbon 18 column (Acclaim, 2.5 \(\upmu\)m, 150 \(\times\) 4.6 mm ID; Thermo Fisher, Bremen, Germany) at 27 \({}^{\circ}\)C. The detection wavelengths used were 254, 280, 330, and 354 nm, and detectors were set from 200-800 nm. The mobile phases were 99% water with 1% formic acid (A) and 1% formic acid in acetonitrile (B). The gradient program started at zero and continued as follows: 5% B, followed by an isocratic 5% B for 5 min, then up to 30% B maintained for 10 min, then to 70% B for 5 min, isocratic at 70% B for 10 min, and finally returning to initial conditions and left for 12 min for column equilibration before each injection. The flow rate was 0.80 mL/min, and the injection volume was 15 \(\upmu\)L. Standards and extracts dissolved in methanol were stored at 10 \({}^{\circ}\)C in the autosampler. The HESI II and Orbitrap spectrometer parameters were set as previously reported [27]. Briefly, the flow rate of Sheath gas was 75 units, the flow rate used for auxiliary gas was 20, the capillary temperature was 400 \({}^{\circ}\)C, the heater temperature of the auxiliary gas was 500 \({}^{\circ}\)C, the spray voltage was 2500 V (for ESI\(-\)), and the S lens, RF level was 30. Full scan data in positive and negative modes were taken at a resolving power of 70,000 FWHM at \(m\)/\(\varepsilon\) 200. The scan range was 100-1000 \(m\)/\(\varepsilon\), the automatic gain control was set to 3 \(\times\) 10\({}^{6}\), and the injection time was 200 ms. The chromatographic system was coupled to MS with a source heated electro-nebulization ionization probe (HESI II). A nitrogen gas carrier (purity \(>\) 99.999%) was produced in a Genius NM32 LA (Peak Scientific, Billerica, MA, USA) generator and used as a collision and damping gas. Mass calibration for Orbitrap was performed once a day, in both negative and positive modes, to ensure a working mass of 5 ppm for accuracy. For the positive mode, a mixture of caffeine (1 mg/mL, 20 \(\upmu\)L) and N-butylamine (1 mg/mL, 100 \(\upmu\)L) was used, and a mixture of sodium dodecyl sulfate (1 mg/mL, 100 \(\upmu\)L) and taurocholic acid sodium salt (1 mg/mL, 100 \(\upmu\)L) (Sigma-Aldrich, Darmstadt, Germany) was used for the negative mode, along with Ultramark 1621 (Alpha Aezar, Stevensville, MI, USA) as the reference compound (at 1 mg/mL, 100 \(\upmu\)L). These compounds were mixed with water:methanol (1:1), acetic acid (100 \(\upmu\)L), and acetonitrile (5 mL) to make a final volume of 5 mL (Merck, Santiago, Chile), and 25 \(\upmu\)L of the mixture was infused using a Chemyx Fusion (Thermo Fisher Scientific, Bremen, Germany) 100 \(\upmu\)L syringe pump. Tentative identification of the metabolites was carried out using full scan mass spectra, fragmentation patterns, the retention index, base peaks chromatograms, and database such as the MassBank of North America (MoNA).