Drimys winteri J.R. (Winteraceae) produce drimane sesquiterpenoids with activity against Candida yeast. In this work, drimenol, polygodial (1), isotadeonal (2), and a new drimane α,β-unsaturated 1,4-dialdehyde, named winterdial (4), were purified from barks of D. winteri. The oxidation of drimenol produced the monoaldehyde drimenal (3). These four aldehyde sesquiterpenoids were evaluated against six Candida species isolated from candidemia patients in Chilean hospitals. Results showed that 1 displays fungistatic activity against all yeasts (3.75 to 15.0 µg/mL), but irritant effects on eyes and skin, whereas its non-pungent epimer 2 has fungistatic and fungicide activities at 1.9 and 15.0 µg/mL, respectively. On the other hand, compounds 3 and 4 were less active. Molecular dynamics simulations suggested that compounds 1–4 are capable of binding to the catalytic pocket of lanosterol 14-alpha demethylase with similar binding free energies, thus suggesting a potential mechanism of action through the inhibition of ergosterol synthesis. According to our findings, compound 2 appears as a valuable molecular scaffold to pursue the future development of more potent drugs against candidiasis with fewer side effects than polygodial. These outcomes are significant to broaden the alternatives to treat fungal infections with increasing prevalence worldwide using natural compounds as a primary source for active compounds.

Fungal biotransformation is an attractive synthetic strategy to produce highly specific compounds with chemical functionality in regions of the carbon skeleton that are not easily activated by conventional organic chemistry methods. In this work, Cladosporium antarcticum isolated from sediments of Glacier Collins in Antarctica was used to obtain novel drimane sesquiterpenoids alcohols with activity against Candida yeast from drimendiol and epidrimendiol. These compounds were produced by the high-yield reduction of polygodial and isotadeonal with NaBH₄ in methanol. Cladosporium antarcticum produced two major products from drimendiol, identified as 9α-hydroxydrimendiol (1, 41.4 mg, 19.4% yield) and 3β-hydroxydrimendiol (2, 74.8 mg, 35% yield), whereas the biotransformation of epidrimendiol yielded only one product, 9β-hydroxyepidrimendiol (3, 86.6 mg, 41.6% yield). The products were purified by column chromatography and their structure elucidated by NMR and MS. The antifungal activity of compounds 1–3 was analyzed against Candida albicans, C. krusei and C. parapsilosis, showing that compound 2 has a MIC lower than 15 µg/mL against the three-pathogenic yeast. In silico studies suggest that a possible mechanism of action for the novel compounds is the inhibition of the enzyme lanosterol 14α-demethylase, affecting the ergosterol synthesis.

Skin cancer is increasing worldwide, with melanoma being its most aggressive and lethal form due to its high metastatic potential. Despite therapeutic advances, drug resistance remains a challenge, highlighting the need to explore new anticancer agents. Leptocarpha rivularis is a native plant of Chile, locally called “Palo negro”, and is traditionally used in medicine by the Mapuche people. L. rivularis produces bioactive germacrene sesquiterpenoids with cytotoxic, antioxidant, anti-inflammatory and anti-angiogenic properties. This study reports for the first time the isolation of ovatifolin from aerial parts of L. rivularis and its identification by NMR and X-ray diffraction, together with its antiproliferative activity against two melanoma cell lines. The results show that ovatifolin has cytotoxic activity against the cell lines A2058 and A375, with an IC₅₀ of 27.6 (90.2 µM) and 18.4 µg/mL (60.1 µM), respectively, evaluated by live-cell IncuCyte^® analysis. Moreover, ovatifolin arrests colony formation in a clonogenic assay, with an IC₅₀ of 3.26 (10.6 μM) and 3.65 µg/mL (11.9 μM) in these same cell lines. Therefore, ovatifolin increased intracellular ROS and decreased the mitochondrial membrane potential (ΔΨ m). Cell death studies using Annexin V showed that its cytotoxic activity is partially caused by non-specific apoptosis, which was corroborated by the caspase inhibitor Z-VAD with an incomplete recovery of the cell death process.

Neurodegenerative diseases remain a major therapeutic challenge, with oxidative stress playing a central role in central and peripheral immune system dysfunction that leads to neuronal loss. Natural products from extreme environments represent an underexplored source of neuroprotective agents. In this study, viridicatin, a quinoline-derived alkaloid, was isolated from the Antarctic fungus Penicillium sp. collected from sediments taken from Deception Island, and its structure was unambiguously confirmed by 1D/2D-NMR spectroscopy and single-crystal X-ray diffraction. Viridicatin (100 µM) significantly attenuated H₂O₂-induced cytotoxicity in HMC-3 human microglial cells, preserving cell viability and mitochondrial membrane potential. Viridicatin modulated the Nrf2 antioxidant signaling pathway, accompanied by increased expression of the downstream antioxidant enzymes HO-1 and NQO1. Moreover, molecular docking revealed preferential binding to the KEAP1 Kelch domain (−8.0 kcal/mol), suggesting indirect Nrf2 pathway modulation. A 100 ns molecular dynamics simulation with MM-GBSA analysis supported the stability of the viridicatin–KEAP1 complex. Notably, viridicatin rescued peripheral immune cells, i.e., peripheral blood mononuclear cells (PBMCs) obtained from older adults with mild cognitive impairment from H₂O₂-induced cell death, bridging the gap between in vitro mechanistic evidence and clinically relevant human cellular models. This is the first report of neuroprotective activity for viridicatin, positioning this Antarctic-derived alkaloid as a compelling candidate for further preclinical development against age-related neurodegeneration.