In vitro susceptibility of Aspergillus spp. to dithiocarbamate organoruthenium compounds

Abstract

The in vitro antifungal activity of ruthenium dithiocarbamate compounds (1-5) was investigated and assessed for its activity against seven different species of Aspergillus (Aspergillus clavatus, Aspergillus flavus, Aspergillus fumigatus, Aspergillus niger, Aspergillus nomius, Aspergillus tamarii and Aspergillus terreus). Analysis of in vitro susceptibility was performed using broth microdilution assay following the Clinical and Laboratory Standards Institute guidelines for filamentous fungi. The cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Aspergillus clavatus and A. fumigatus were more susceptible species for complexes 1 and 2. Other complexes showed excellent minimum inhibitory concentration (4-64 μg ml(-1)) against most microorganisms. Complexes 1 and 2 are respectively 180- and 95-fold more active than the corresponding free ligands against A. clavatus and the complex 5 is 46-fold more active than free ligand against A. niger. Aspergillus niger was more susceptible to the action of the complexes 1 and 5 (16 μg ml(-1)). A low cytotoxic activity (IC(50) > 10(-6) mol l(-1) ) on normal mammalian cells (BHK-21) to the evaluated complexes was measured. Ruthenium complexes are promising antifungal agents against the development of novel effective drug against different species of Aspergillus; however, for A. nomius and A. terreus, they were not active in the highest concentration tested.

In Vitro Studies of the Activity of Dithiocarbamate Organoruthenium Complexes against Clinically Relevant Fungal Pathogens

“…All dithiocarbamate ligands L1 – L9 were synthesized in good yields (63%–93%) as described elsewhere [42,50] through the usual procedure starting from the corresponding substituted amines and carbon disulfide (CS 2 ); all ligands were obtained as pure products and have been well-characterized by the usual techniques (IR, ESI-MS, 1 H and 13 C-NMR spectra and elemental analysis). The coordination reaction between ruthenium (III) trichloride and the nine recently prepared dithiocarbamate ligands ( L1 – L9 ) (1:3 mol/mol, in ethanol) afforded nine pentakis(dithiocarbamate)diruthenium complexes C1 – C9 ( C1 : N , N -dimethyl - ; C2 : N , N -diethyl-; C3 : N -mono- tert- butyl-; C4 : N -mono-( iso- propyl)-; C5 : N -di-( iso- propyl)-; C6 : N -pirrolidinyl-; C7 : N -piperidinyl-; C8 : N -morpholinyl- and C9 : N , N -dibenzyl-dithiocarbamates) in 65%–79% yield.…”

“…The coordination reaction between ruthenium (III) trichloride and the nine recently prepared dithiocarbamate ligands ( L1 – L9 ) (1:3 mol/mol, in ethanol) afforded nine pentakis(dithiocarbamate)diruthenium complexes C1 – C9 ( C1 : N , N -dimethyl - ; C2 : N , N -diethyl-; C3 : N -mono- tert- butyl-; C4 : N -mono-( iso- propyl)-; C5 : N -di-( iso- propyl)-; C6 : N -pirrolidinyl-; C7 : N -piperidinyl-; C8 : N -morpholinyl- and C9 : N , N -dibenzyl-dithiocarbamates) in 65%–79% yield. The complete chemical characterization was made by several physicochemical techniques (measurement of magnetic susceptibility (μeff), electron paramagnetic resonance (EPR) spectra, conductivity, cyclic voltammetry) and spectrometric methods (IR, ESI-MS, 1 H and 13 C-NMR spectra) [50,59,60,61,62]. All compounds were obtained in high purity level (TLC, HPLC and ESI(+)-MS) and the analysis of the results obtained by ESI-(+)-MS spectrometry suggested the general formula of [Ru 2 ( Ln ) 5 ] for all diruthenium pentadithiocarbamate complexes.…”

“…]. Nevertheless, the first work that describes the investigation of dithiocarbamate ruthenium (III) complexes as antifungal agent [50] has been developed by our own research group, and in this work the susceptibility of seven different species of Aspergillus ( A. clavatus, A. flavus, A. fumigatus (ATCC 16913 and CI, clinical isolated), A. niger , A. nomius , A. tamarii and A.terreu s) was tested with promising results considering that Aspergillus spp. has also became a recognized pathogen related to IFIs [51,52].…”

“…has also became a recognized pathogen related to IFIs [51,52]. It is remarkable that in some cases [43,50] the ruthenium complexes showed higher activity than the corresponding free ligands. In fact, the study of metal-based drugs represent a therapeutic alternative for novel drug discovery [53,54] and in this way ruthenium complexes provide a rich platform and suitable building blocks for the design of novel bioactive compounds, once the biological activity of the organic ligand is known, due to the specific properties inherent of the transition metal center [55,56].…”

Metal Complexes of Dithiocarbamate Derivatives and its Biological Activity

“…Monitoring of the antifungal activities of the complexes of transition metal with dithiocarbamates, ruthenium dithiocarbamate compounds were synthesized ( Fig. 14) and evaluated as well for the antifungal activities against 8 isolates of Aspergillus, that comprises 7 distinct kinds, such as, Aspergillus clavatus, A. flavus, A. fumigatus, A. niger, A. nomius, A. tamarii and A. terreus [40]. One of the surveys of small molecule therapeutic elements has shown that most of those therapeutics result from an analogue based method and that their market value comprises two-third of the entire drug sales [41].…”