Levoglucosenone-Derived Isothiocyanates as Antifungal Compounds: Merging Sustainability and Medicinal Chemistry

The increasing generation of agricultural biomass waste constitutes a significant environmental and climatic concern, while simultaneously offering opportunities for its valorization into high-value products. Levoglucosenone, a cellulose-derived platform molecule, provides access to structurally distinctive bicyclic acetals with considerable relevance in medicinal chemistry. In this study, we investigated the synthesis and antifungal properties of novel isothiocyanate derivatives incorporating the 6,8-dioxabicyclo[3.2.1]octene scaffold. A synthetic approach based on the introduction of a thiocyanate group, followed by a [3,3]-sigmatropic rearrangement, enabled the efficient preparation of two isothiocyanate derivatives. Optimization of reaction conditions led to improved yields, while comprehensive structural characterization confirmed the regio- and stereoselective nature of the transformations. Biological evaluation demonstrated broad-spectrum antifungal activity against clinically relevant pathogens, including Candida, Cryptococcus, Aspergillus, and dermatophytes, with compound 7 consistently exhibiting superior potency. Both compounds displayed fungicidal activity and effectively inhibited key virulence factors at sub-inhibitory concentrations. In particular, they impaired Candida albicans morphogenesis and suppressed urease activity and melanin production in Cryptococcus species, without affecting capsule formation. These findings underscore the potential of levoglucosenone-derived isothiocyanates as promising scaffolds for antifungal drug development, combining potent growth inhibition with the ability to disrupt critical pathogenic mechanisms.