Desenvolvimento de novos agentes leishmanicidas baseados em complexos de metais de cunhagem com ligantes híbridos sulfonamidas/tioureias

Abstract

Leishmaniasis are a group of parasitic diseases with the potential to infect more than 1 billion people living in endemic areas. However, they are still among the most neglected diseases in the world, with an old and inadequate treatment. In order to the improvement of this panorama, this work consists in the synthesis and characterization of complexes derived from coinage metals ions (CuI, AgI and AuI) with thiosemicarbazides derived of the p-toluenesulfohydrazide aiming to obtain potential leishmanicidal agents. The thiosemicarbazides (HL1Ch, HL2Ph, HL3FPh, HL4ClPh, HL5NO2Ph, HL6Al and HL7SfNa) were obtained through reactions involving equimolar solutions of the p-toluenesulfohydrazide with the R-isothiocyanates (R = cyclohexyl, phenyl, p-fluorophenyl, p-chlorophenyl, p-nitrophenyl, allyl and sodium benzenesulfonate) of interest, in order to obtain hybrid molecules containing two biologically active classes: sulfonamides and thioureas. The ligands HL1-6 were used in complexation reactions with different metal precursors forming complexes of composition [Cu(PPh3)2(LR)], [{Cu(HLR)(CH3CN)}2μ-(HLR)2](CF3SO3)2, [Ag(HLR)2]NO3, [Ag(HLR)2]CF3SO3, [{Ag(HLR)}2μ-(HLR)2](CF3SO3)2 and [Au(HLR)2]Cl. The compounds obtained were analyzed by several techniques, such as: absorption spectroscopy in the infrared region, Nuclear Magnetic Resonance (1H, 31P and 19F), ultraviolet-visible, emission spectroscopy, high resolution mass spectrometry and cyclic voltammetry. Additionally, the complexes were studied by single crystal X-ray diffraction, revealing linear and tetrahedral structures for the AuI and CuI centers, respectively. Density Functional Theory calculations were also performed to understand the nature of the orbitals involved in the excited state transitions of the complexes. Furthermore, molecular docking studies showed which complexes are energetically more favorable to interact with the Old Yellow enzyme of the Leishmania braziliensis (LbOYE). In this sense, in vitro biological tests showed that the complexes [Ag(HL4ClPh)2]NO3 and [Ag(HL5NO2Ph)2]NO3 show high activity against the strains of the Leishmania infantum and Leishmania braziliensis, when compared to the standard drug Glucantime. Finally, experimental studies of interaction with LbOYE revealed that this could be one of the targets of the AgI and AuI compounds.