Abstract:The in vitro antifungal activity of nine dirutheniumpentadithiocarbamate complexes C1-C9 was investigated and assessed for its activity against four different fungal species with clinical interest and related to invasive fungal infections (IFIs), such as Candida spp. influence from steric and lipophilic parameters in the antifungal activity can be noticed. Cytotoxicity assays (IC 50 ) showed that the complexes are not as toxic (IC 50 values are much higher-30 to 200 fold-than MIC values). These ruthenium complexes are very promising lead compounds for novel antifungal drug development, especially in IFIs, one of most harmful emerging infection diseases (EIDs).

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.

Sodium adducts of six organosulfur-α,ω-ditetrazole compounds (Tz-(CH(2))(n)-S(O)(m)-(CH(2))(n)-Tz; where Tz = tetrazole ring; n = 2, 3; m = 0, 1, 2) were generated via electrospray ionization (ESI) and their fragmentation pattern assessed via collision-induced dissociation (CID). Two main dissociation channels were observed: (a) losses of N(2) and HN(3) from the tetrazole rings; (b) cleavage of the C-S bond. The sulfoxides pass predominantly through the second fragmentation pathway, but for the sulfides and sulfones the tetrazole ring fragmentation occurs. Theoretical calculations at the B3LYP/6-31 + G(d,p) level indicate that for all the adducts (sulfide, sulfoxide, and sulfone) the dissociation pathway that leads to product ions arising from loss of N(2) was the most exothermic. Based on these results and assumptions, it was postulated that the dissociation of the sulfoxide adducts occurs under kinetic control (N(2)-loss pathway via a much more energetic transition state). For the sulfide and sulfone adducts, on the other hand, the dissociation process takes place via a thermodynamically controlled process.

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The in vitro antifungal activity of six thioureido substituted amines (P1-P6) was evaluated against Candida species, including Candida albicans, C. glabrata, C. krusei and C. parapsilosis. These tri- and tetra-thioureido amino derivatives with different methylation levels were synthesised through easy synthetic routes to evaluate their antifungal properties against Candida species. Among all studied derivatives, the tri-(2-thioureido-ethyl)-amine (P1) was the most active compound inhibiting C. albicans and C. glabrata at a concentration of 0.49 μg ml(-1); P3, the N,N',N'',N'''-hexamethyl-derivative, also showed inhibitory activity against C. albicans and C. glabrata, but in higher concentrations (250 μg ml(-1) ). The N,N',N'',N'''-tetramethylated amine (P5) only inhibited the growth of C. glabrata, but its corresponding N,N',N'',N'''-octamethyl derivative (P6) was also active against C. glabrata (125 μg ml(-1)) and it was the only compound active against C. parapsilosis. P2 and P4 showed no significant antifungal activity. The structure-activity relationship of the thioureido-substituted derivatives indicates that the molecular branching and the alkylation levels can influence the antifungal activity. This study demonstrated that thioureido derivatives exhibited significant antifungal activity against Candida species and that they can be considered as a very promising bioactive lead compound to develop novel antifungal agents.

This mini-review presents a brief introduction about the history of Medicinal Chemistry and the importance of lipophilicity in this development; among others the contributions of Hippocrates, Galeno, Paracelsus, Overton, Ehrlich and Hansch are remarkably noticed.Keywords: history of medicinal chemistry; Hippocrates; Galeno; Paracelsus; Overton; Hansch; lipophilicity ResumoO presente artigo, apresentado como mini-revisão, mostra uma breve introdução sobre a história da Química Medicinal e a importância da influência da lipofilia no desenvolvimento de medicamentos evidenciando, dentre outras, as contribuições de Hipócrates, Galeno, Paracelsus, Overton, Ehrlich e Hansch.