Design and synthesis of betulinic acid–dithiocarbamate conjugates as potential antifungal agents against Candida albicans†

Abstract

Diverse betulinic acid–dithiocarbamate conjugates were designed and synthesized via a two-step reaction at room temperature. Among the fourteen dithiocarbamate analogs of betulinic acid, DTC2 demonstrated the best antifungal activity against Candida albicans, with a minimum inhibitory concentration (MIC) of 4 μg mL⁻¹, achieving 99% fungicidal activity at the same concentration. These compounds were found to be ineffective against common Gram-negative and Gram-positive pathogens, suggesting their specificity to fungi. Furthermore, DTC2 exhibited synergistic effects with the antifungal drugs fluconazole and nystatin, resulting in a significant decrease in MIC by 64 and 16 folds, respectively, when co-administered. Notably, the molecule also hindered hyphae formation in Candida albicans, thereby reducing its pathogenicity. Furthermore, it displayed time- and concentration-dependent kill kinetics, sterilizing C. albicans within 8 hours at 8× MIC. Additionally, DTC2 exhibits greater efficacy against β-carbonic anhydrase with better docking scores and binding patterns than ethoxyzolamide, a well-known inhibitor of β-carbonic anhydrase.