Estudo da atividade leishmanicida de novos complexos de Sb(III) e Bi(III) com ligantes polipiridínicos

Abstract

The activity of a series of polypyridyl compounds 2,2 '-bipyridine (bipy),1,10-phenanthroline (Phen), dipyrido [3,2-d: 2', 3'-f]quinoxaline (dpq) anddipyrido [3 0.2-a: 2 ', 3'-c]phenazine (dppz) was evaluated in vitro againstthe promastigote form of Sb(III)-sensitive and resistant Leishmaniainfantum chagasi and Leishmania amazonensis strains. All compounds were more active than potassium antimony tartrate, used as control drug. The bipy, Phen and dpq showed inhibitory concentration IC50 values in the nanomolar range. Two novel trivalent antimony(III) and bismuth(III) complexes with the nitrogen-donor heterocyclic ligand dipyrido[3,2-a:2',3'-c]phenazine (dppz) were synthesized and characterized as [Sb(dppz)Cl3]·H2O·CH3OH and [Bi(dppz)Cl3]. The crystal structure of Sb(III) complex was determined by X-ray crystallography. These complexes were evaluated for their activityagainst the promastigote form of Sb(III)-sensitive and resistantLeishmania strains. Both complexes were more effective than dppz alone in inhibiting the growth of Leishmania promastigotes and were at least 77 and 2400 times more active than potassium antimonyl tartrate in Sb(III)- sensitive and -resistant Leishmania, respectively. The cytotoxicity of dppz and its complexes against mouse peritoneal macrophages occurred at dppz concentrations at least 6-fold greater than those found to be active against Leishmania promastigotes. To investigate the role of the metal in the improved antileishmanial activity of dppz, the activity of the Sb(III) complex was compared between the Sb-resistant mutants and their respective parental sensitive strains. The lack of cross-resistance to the Sb(III)-dppz complex together with the much lower activity of antimonyl tartrate, SbCl3 and BiCl3 strongly support the model that the metal is not active by itself but improves the activity of dppz through complexation.Five Sb(III) complexes with 2,2'-bipyridine (bipy), 1,10-phenanthroline(Phen), dipyrido [3,2-d: 2',3'-f]quinoxaline (dpq) were prepared andcharacterized as: [Sb(bipy)Cl3], [Sb(bipy)Cl2], [Sb(Phen)Cl3],[Sb(Phen)Cl2] e [Sb(dpq)Cl3]. The crystal structures of the complexes with 1,10-phenanthroline were determined for the first time by X ray diffraction. These complexes were evaluated for their activity against Sb(III)-sensitive and resistant Leishmania promastigotes. The leishmanicidal activities of these complexes were higher than those of potassium antimonyl tartrate. All the complexes obtained from the SbCl3 salt were more active than the salt itself. On the other hand, than SbCl2 salt was found to be highly active and more effective than the[Sb(bipy)Cl2] complex. The coordination of Sb (III) caused a significant improvement in the activity of Phen complex against parasites of L. infantum chagasi. Studies of the interaction of these compounds with a peptide model of the zinc finger domain of the HIV-1 NCp7 proteín (KGC), showed that these complexes formed new species with the peptide. Studies of Phen interaction with the Zn(II)-KGC system, indicated that Phen induceds the ejection of Zn(II) from the zinc finger domain.