Exploration of Dithiocarbamate-Linked Kojic Acid–Piperazine Hybrids: Synthesis, Characterization, and Biological Screening

Abstract

Developing drug candidates with multiple mechanisms of action is a strategy to overcome drug resistance, the main obstacle in effectively treating infections. This study focused on the design and synthesis of hybrid compounds containing kojic acid scaffold and substituted phenylpiperazine groups linked via a dithiocarbamate moiety. Structural elucidation was achieved using spectroscopic techniques and elemental analysis. The single-crystal X-ray diffraction (SCXRD) analysis and density functional theory (DFT)-based geometry optimization were performed. Antimicrobial activities were assessed against bacteria and fungi through disk diffusion and microdilution techniques. Their influence on biofilm production was measured spectrophotometrically. Additionally, the antioxidant potential was screened using the 2,2’-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+) radical decolorization assay and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. According to bioactivity results, compound 3—named (5-hydroxy-4-oxo-4H-pyran-2-yl)methyl 4-(3-chlorophenyl)piperazine-1-carbodithioate—exhibited the most potent antifungal activity against clinical isolates of Candida albicans with a mean minimum inhibitory concentration (MIC) of 64 µg/mL and a mean inhibition zone diameter value of 14–15 mm. Also, compound 4 demonstrated the highest biofilm inhibition rates (70.5%) against C. albicans and displayed strong antioxidant capacity against ABTS+ (IC₅₀ = 8.75 µg/mL). This study's results could help in creating new drug candidates targeting bacterial infections linked to biofilms that require strong antioxidant activity.