Abstract

Candidaspecies 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-albicansCandidaspecies such asC. glabrata, C. parapsilosis, C. aureus,andC.kruseiare limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties againstCandidayeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (C1) from barks ofDrimys winteriand used it as starting material for the hemi-synthesis of four sesquiterpenoids by oxidation with pyridinium chlorochromate (PCC). The structure of the products (C2,C3,C4,andC5) was elucidated by 1D and 2D NMR spectroscopy resulting inC4being a novel compound. Antifungal activity assays againstC. albicans, C. glabrata,andC. kruseirevealed thatC4exhibited an increased activity (IC(50)of 75 mu g/mL) compared toC1(IC(50)of 125 mu g/mL) in all yeast strains. The antifungal activity ofC1andC4was 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 thatC1andC4bind to the outermost region of the catalytic site of 14-alpha demethylase and block the entrance of lanosterol (LAN) to the catalytic pocket. Binding free energy estimates suggested thatC4forms a more stable complex with the enzyme thanC1, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control ofCandidaspecies as inhibitors of 14-alpha demethylase.