| Summary: | <i>Candida</i> species cause an opportunistic yeast infection called Candidiasis, which is responsible for more than 50,000 deaths every year around the world. Effective treatments against candidiasis caused by non-albicans <i>Candida</i> species such as <i>C. glabrata, C. parapsilosis, C. aureus,</i> and <i>C.</i> <i>krusei</i> are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against <i>Candida</i> yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (<b>C1</b>) from barks of <i>Drimys winteri</i> and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (<b>C2</b>, <b>C3</b>, <b>C4,</b> and <b>C5</b>) was elucidated by 1D and 2D NMR spectroscopy resulting in <b>C4</b> being a novel compound. Antifungal activity assays against <i>C. albicans, C. glabrata,</i> and <i>C. krusei</i> revealed that <b>C4</b> exhibited an increased activity (IC<sub>50</sub> of 75 μg/mL) compared to <b>C1</b> (IC<sub>50</sub> of 125 μg/mL) in all yeast strains. The antifungal activity of <b>C1</b> and <b>C4</b> was rationalized in terms of their capability to inhibit lanosterol 14-alpha demethylase using molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations. In silico analysis revealed that <b>C1</b> and <b>C4</b> bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (<b>LAN</b>) to the catalytic pocket. Binding free energy estimates suggested that <b>C4</b> forms a more stable complex with the enzyme than <b>C1</b>, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of <i>Candida</i> species as inhibitors of 14-alpha demethylase.
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