Evaluation of Some 3-Substituted Rhodanine Derivatives as Anti-Candida Agents with Ferric Reducing Capacity

The increasing prevalence of fungal infections caused by Candida species, together with rising antifungal resistance, highlights the urgent need for novel therapeutic agents with improved efficacy and safety. In this study, a series of 3-substituted rhodanine derivatives (3–6) were synthesized and evaluated as potential multifunctional compounds combining antifungal activity and ferric reducing capacity in the FRAP assay. The compounds were characterized using FT-IR and NMR spectroscopy and assessed for their physicochemical and pharmacokinetic profiles through in silico ADME analysis. Biological evaluation revealed that compounds 3 and 5 exhibited the most promising antifungal activity against a panel of clinically relevant Candida strains, with compound 5 demonstrating broad-spectrum, predominantly fungicidal effects. In contrast, compounds bearing a bulky 4-chlorobenzoyl substituent (4 and 6) showed reduced activity, indicating the importance of structural features for antifungal efficacy. Ferric reducing capacity assessment using the FRAP assay confirmed that all compounds possess reducing activity, with compounds 3 and 6 showing the highest potential. Safety evaluation using zebrafish (Danio rerio) embryos and larvae revealed concentration-dependent toxicity for all compounds. Notably, compounds 5 and 6 exhibited significant embryotoxicity and neurobehavioral effects at low micromolar concentrations, whereas compound 3 demonstrated a more favorable safety profile, with minimal impact on development and locomotor activity. Taken together, these results indicate that compound 3 provides a balanced combination of antifungal activity and reduced toxicity, while compound 5 represents a highly active but more toxic derivative. The observed structure–activity relationships emphasize the importance of carefully tuning substituent-dependent properties to optimize both biological activity and safety, supporting the continued investigation of rhodanine-based multifunctional antifungal agents targeting fungal proliferation and ferric reducing properties.