Discovery of semisynthetic derivatives of (R)- and (S)-usnic acids as potential antifungal agents against C. tropicalis and T. rubrum†

The prevalence of human fungal infections (FIs) is rapidly increasing worldwide, posing substantial challenges to public health. The underestimation of FIs risk led to a limited knowledge of the fungal pathogenicity and a concomitant paucity of antimycotic drugs that are increasingly unable to effectively address resistance liabilities. The identification of innovative antifungal drugs is therefore an urgent need. Natural products have always been under scrutiny in the drug discovery process. Of these, usnic acid (UA) represents a compelling starting point for antifungal drug development due to its natural occurrence as a secondary metabolite in various lichen species, where it serves as a natural defence mechanism against fungal invasion. This dibenzofuran derivative possesses an intrinsically rigid three-dimensional architecture with stereogenic center, providing a pre-organized chiral scaffold with potential for selective interaction with fungal targets. Despite its high therapeutic potential as antimicrobial agent, UA suffers from poor solubility and hepatotoxicity issues. The proposed research explores the modification of UA scaffold to generate the series of semisynthetic compounds 1–9 by derivatizing the (R)- and (S)-UA as enamines. Considering the inherent chirality of UA, this work aims to identify structure–activity relationships that optimize antifungal efficacy while improving the pharmacokinetic properties of UA. The resulting compounds were evaluated for their antifungal activity against three strains, showing significant differences in potency concerning their absolute configuration. This research addresses the urgent need for novel antifungal agents in an era of increasing resistance to conventional treatments, identifying (9bS,15S)-1, 3, 4, and 8 compounds as promising compounds for developing antifungal therapeutics.