Novel carbazole-triazole conjugates as DNA-targeting membrane active potentiators against clinical isolated fungi

A series of carbazole-triazole conjugates were designed, synthesized and characterized by IR, NMR, and HRMS spectra. Biological assay showed that most of the synthesized compounds exhibited moderate and even strong antifungal activities, especially 3,6-dibromocarbazolyl triazole 5d displayed excellent inhibitory efficacy against most of the tested fungal strains (MIC = 2–32 μg/mL) and effectively fungicidal ability towards C. albicans, C. tropicals and C. parapsilosis ATCC 22019 (MFC = 4–8 μg/mL). Its combination use with fluconazole could enhance the antifungal efficacy, and compound 5d also did not obviously trigger the development of resistance in C. albicans even after 10 passages. Preliminary mechanism study revealed that the active molecule 5d could depolarize fungal membrane potential and intercalate into DNA to possibly block DNA replication, thus possibly exhibiting its powerful antifungal abilities. Conjugate 5d could interact with HSA, which was constructive for the further design, modification and screening of drug molecules. Docking investigation demonstrated a non-covalent binding of 5d with CYP51 through hydrogen bond and hydrophobicity. These results strongly suggested that compound 5d could act as a potential template for the development of promising antifungal drugs. A novel type of potential antifungal carbazole-triazole conjugates was developed, and their antifungal efficacy and possible action mechanism were investigated. [Display omitted] •Novel carbazole-triazole conjugate 5d could depolarize membrane potential and intercalate into DNA to reveal fungicidal potentiality.•Compound 5d indicated synergistic effect with fluconazole and was fungicidal against C. albicans, C. tropicals and C. parapsilosis ATCC 22019.•Compound 5d did not obviously trigger resistance development in fungi.•Compound 5d could depolarize membrane potential and intercalate into DNA to block DNA replication.•Compound 5d could non-covalently interact with HSA and bind with CYP51 through hydrogen bond and hydrophobicity.