Antifungal Efficacy against Candida spp. Strains and Synthesis via Heck-Matsuda Arylation of Aryl-Camphene-Type Derivatives.

The rapid growth of fungal infections caused by Candida spp. associated with antimicrobial resistance requires the development of new therapeutic approaches to combat these infections. Camphene is a compound derived from the essential oils of various plants and has antimicrobial properties. Based on this, the objective of this study was to carry out the late-stage diversification of camphene by means of highly stereoselective Heck-Matsuda (HM) arylation and to evaluate the antifungal activity of these derivatives against Candida spp. The reaction provided direct access to seven aryl-camphene derivatives (adducts HM 3a-g) with good to excellent yields (48-98%) in short reaction times under moderate and aerobic conditions. For the antifungal tests, camphene and the HM adducts 3a and 3b, with the highest yields, were selected. Of the compounds, camphene showed the best intrinsic antifungal activity, outperforming fluconazole (FCZ) againstC. albicans. In association with FCZ, camphene and HM adduct 3a significantly potentiated the drug's action, resulting in a notable reduction in the average inhibitory concentration (IC50). Tests to determine the minimum fungicidal concentration showed that only the combination of camphene and FCZ showed fungicidal action againstC. albicans. ForC. tropicalis, there was fungicidal activity with the combinations of camphene and FCZ, and HM adduct 3a and FCZ. The morphological transition from yeast to hyphae and/or pseudohyphae inC. albicans was inhibited only by camphene. InC. tropicalis, filamentation was completely inhibited by the action of camphene and its derivatives at the concentrations evaluated. Taken together, these results suggest that camphene and its HM adducts (3a-b) evaluated may be promising candidates for the development of antifungal agents, especially in combination therapies with fluconazole.