Oxidation of Isodrimeninol with PCC Yields Drimane Derivatives with Activity against Yeast by Inhibition of Lanosterol 14-Alpha Demethylase.

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 species such as and are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol () from barks of and used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (, , and ) was elucidated by 1D and 2D NMR spectroscopy resulting in being a novel compound. Antifungal activity assays against and revealed that exhibited an increased activity (IC of 75 μg/mL) compared to (IC of 125 μg/mL) in all yeast strains. The antifungal activity of and 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 and bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol () to the catalytic pocket. Binding free energy estimates suggested that forms a more stable complex with the enzyme than , in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of species as inhibitors of 14-alpha demethylase.