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

Biomolecules

Andres Iturra¹  Victor Marin¹  Cristian Paz¹  Verónica A. Jiménez²  Leandro Ortiz³  Andres Opazo⁴  Matthias Heydenreich⁵  Bernd Schmidt⁵ 

[1] Laboratory of Natural Products & Drug Discovery, Department of Basic Science, Universidad de La Frontera, Av. Francisco Salazar 01145, 4780000 Temuco, Chile;Universidad Andres Bello, Sede Concepción, Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Autopista Concepción-Talcahuano 7100, 4030000 Talcahuano, Chile;Universidad Austral de Chile, Instituto de Ciencias Química, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, 5091000 Valdivia, Chile;Universidad de Concepción, Departamento de Microbiología, Laboratorio de Investigación en Agentes Antibacterianos (LIAA), Barrio Universitario S/N, 160-C 1807 Concepción, Chile;Universität Potsdam, Institut für Chemie, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany;

关键词: Isodrimeninol;    PCC oxidation;    Candida yeast;    molecular docking;    lanosterol 14-alpha demethylase;   

DOI  :  10.3390/biom10081101

来源: DOAJ

【 摘 要 】

Candida 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 Candida species such as C. glabrata, C. parapsilosis, C. aureus, and C. krusei are limited due to severe resistance to conventional antifungal drugs. Natural drimane sesquiterpenoids have shown promising antifungal properties against Candida yeast and have emerged as valuable candidates for developing new candidiasis therapies. In this work, we isolated isodrimeninol (C1) from barks of Drimys winteri and 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, and C5) was elucidated by 1D and 2D NMR spectroscopy resulting in C4 being a novel compound. Antifungal activity assays against C. albicans, C. glabrata, and C. krusei revealed that C4 exhibited an increased activity (IC₅₀ of 75 μg/mL) compared to C1 (IC₅₀ of 125 μg/mL) in all yeast strains. The antifungal activity of C1 and C4 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 C1 and C4 bind 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 that C4 forms a more stable complex with the enzyme than C1, in agreement with the experimental evidence. Based on this new approach it is possible to design new drimane-type sesquiterpenoids for the control of Candida species as inhibitors of 14-alpha demethylase.

【 授权许可】

Unknown