Atividade de compostos porfirínicos como catalisadores na oxidação de carvacrol e como potenciais agentes leishmanicidas

Abstract

Porphyrin compounds are essential for life on Earth and perform diverse biological activities in in vivo systems. Thus, bioinspired synthetic compounds combined with the chemistry of antimony(V) and manganese(III) ions may represent excellent candidates for drugs in the fight against leishmaniasis and in their application as catalysts in oxidation reactions, respectively. In this work, the porphyrin compounds H2T245TMPP, [MnIIICl(TPP)], [MnIIICl(T245TMPP)], [SbVCl2(T245TMPP,)]Cl and [SbVCl2(T35DMPP)]Cl were synthesized and characterized by absorption spectroscopy in the ultraviolet- (UV-VIS), hydrogen nuclear magnetic resonance (1H NMR, except manganese complex), mass spectrometry and elemental analysis. These techniques alowed for confirming the obtaining of the compounds of interest. About catalysis studies, manganese complexes were used in carvacrol oxidation reactions, in the presence of PhIO and PhI(OAc)2 oxidants, in dimethyl carbonate, dichloromethane, and ethyl acetate solvents. Overal, carvacrol conversion was in the range of 93-100%. Systems with PhI(OAc)2 and dimethyl carbonate, a green solvent, showed higher carvacrol conversion values. Thymoquinone, a product exclusively formed in other systems described in the literature, was obtained with low yields (less than 8%), the major product in the studied systems being a polymer of carvacrol. Through the experiments, it was proved that the polymerization reaction of carvacrol is dependent on the metalloporphyrin catalyst, the oxidant, and that this reaction possibly occurs by a radical mechanism. The reuse efficiency of porphyrin catalysts was evaluated in a sequence of four cycles, in the three solvents, in the presence of the oxidant PhI(OAc)2. Free-base porphyrins and antimony complexes had their leishmanicidal activity evaluated against promastigotes and amastigotes of the species Leishmania braziliensis. In tests with the promastigote form, the novel porphyrin [SbVCl2(T245TMPP)]Cl showed greater leishmanicidal activity when compared to the other compounds. However, in the tests with the amastigote form, the porphyrins H2T245TMPP and H2T35DMPP showed greater toxicity to the parasite, with the lowest values of Inhibitory Concentration of 50% (IC50). Comparing the IC50 values of the compounds studied with that described for Miltefosine, the reference drug, showed greater toxicity for the amastigote form of the same species and less cytotoxicity for macrophages (healthy cells). Redox tests were performed for antimony(V) porphyrins in the presence of biological targets, GSH and L-cysteine, to verify a possible reduction of complexes by these biomolecules. The tests were monitored using absorption spectroscopy in the UV-VIS region, and it was found that there was no reduction of antimony(V) to antimony(III), which alows ruling out the occurrence of a mechanism of leishmanicidal action by reduction of the ion Sb(V), as proposed for other compounds. The same compounds used in the leishmanicidal studies were evaluated for their interaction with salmon sperm deoxyribonucleic acid (DNA) using absorption spectroscopy in the UV-VIS region, circular dichroism, and fluorescence emission. Spectral variations were observed and intrinsic binding constants, suppression constants and Stern-Volmer suppression kinetics were calculated for al compounds. The results of the porphyrin-DNA interaction assays point to an external pathway or partial intercalation mode between the nitrogenous bases.