Antifungal Properties of 3-(Morpholin-4-yl)propane-2,3-dione 4-Phenylthiosemicarbazone and Its Mixed Ligand–Copper(II) Complexes Toward Cryptococcus neoformans

The rising incidence of fungal infections and the limited effectiveness of current antifungal drugs emphasize the need for new active substances. Cryptococcus neoformans is a major opportunistic pathogen, responsible for cryptococcal meningitis in immunocompromised patients and associated with high mortality worldwide. Thiosemicarbazones and their metal complexes are reported to exhibit diverse biological activities, including antifungal effects.

For our study, we have synthesized 3-(morpholin-4-yl)propane-2,3-dione 4-phenylthiosemicarbazone (HL) and its mixed ligand–copper(II) complexes [CuL(Im)NO₃], [CuL(Py)NO₃], [CuL(β-Pic)NO₃], and [CuL(γ-Pic)NO₃]. The composition and structure of all compounds were confirmed using ¹H and ¹³C NMR, FTIR, elemental analysis, molar conductivity measurements, and X-ray crystallographic analysis.

The antifungal activity of all synthesized compounds was evaluated towards Cryptococcus neoformans (CECT 1043) using the broth microdilution method. The mixed ligand–copper(II) complexes exhibited higher activity compared to both the HL and the copper(II) nitrate complex from which they were obtained. This finding confirms that the introduction of an additional ligand into the inner coordination sphere can enhance biological activity. The most active compound was [CuL(γ-Pic)NO₃], which showed MIC and MBC values of 7.81 µg/mL and 15.63 µg/mL, respectively.

These results highlight the potential of mixed ligand–copper(II) complexes as promising leads for the development of new antifungal agents, particularly against pathogenic fungi such as Cryptococcus neoformans.

The work was performed with financial support from subprogram 010602 of the institutional project.