Bis(N-picolinamido)cobalt(II) Complexes Display Antifungal Activity toward Candida albicans and Aspergillus fumigatus

Abstract

This report highlights the synthesis and characterization of ten new bis(N-picolinamido)cobalt(II) complexes of the type [(L)₂ CoX₂ ]^0/2+ , whereby L=N-picolinamide ligand and X=diisothiocyanato (-NCS), dichlorido (-Cl) or diaqua (-OH₂ ) ligands. Single crystal X-ray (SC-XRD) analysis for nine of the structures are reported and confirm the picolinamide ligand is bound to the Co(II) center through a neutral N,O binding mode. With the addition of powder X-ray diffraction (PXRD), we have confirmed the cis and trans ligand arrangements of each complex. All complexes were screened against several fungal species and show increased antifungal activity. Notably, these complexes had significant activity against strains of Candida albicans and Aspergillus fumigatus, with several compounds exhibiting growth inhibition of >80 %, and onecompound inhibiting Aspergillus fumigatus hyphal growth by >90 %. Conversely, no antifungal activity was exhibited toward Cryptococcus neoformans and no cytotoxicity towards mammalian cell lines.

Keywords: Aspergillus fumigatus; Bioinorganic Chemistry; Candida albicans; Cobalt Complexes; Picolinamide ligands.

Figure 1

A range of cobalt complexes exhibiting anti‐microbial activity.

Figure 2

Potential isomers of [(L)₂CoX₂] (where L=a picolinamide ligand and X=any one electron ligand), with the cis/trans descriptors designated in the order: ancillary(X,X)‐picolinamide pyridyl ring (N,N)‐picolinamide amide group (O,O).

Scheme 1

Synthetic routes for a) bis(N‐picolinamido)cobalt(II) diisothiocyanato complexes 1–8, b) bis(N‐picolinamido)cobalt(II) dichlorido complex 9 and c) bis(N‐picolinamido)cobalt(II) diaqua complex 10.

Figure 3

Molecular structures of complexes 1, 2, 4–10. Displacement ellipsoids are at the 50 % probability level for heteroatoms only. Hydrogen atoms and counterions are omitted for clarity.

Figure 4

Powder X‐ray Diffraction (PXRD) patterns for complexes 2 (cis) and 4 (trans); black=simulated and blue =experimental.

Figure 5

Cyclic voltammograms of compounds; A. complex 1, B. complex 9 and C. complex 10 in dry DMF/0.1 M NBu₄PF₆; and at a scan rate=100 mV/s. Potentials are reported against ferrocene (Fc/Fc⁺=0.0 V).

Figure 6

A. The average hyphal length of untreated A. fumigatus and following the treatment with compounds 1–10 after 24 h at 37 °C. B. A representative image depicting hyphal growth in the presence or absence of 32 μg ⋅ mL⁻¹ compound 5 after 24 h. Hyphal length was measured using ImageJ and results are representative of 100 germinating fungal spores. Significance was determined by one‐way ANOVA with Dunnett's multiple comparisons. Scale bars represent 20 μm.