Improved Antileishmanial Activity of Dppz through Complexation with Antimony(III) and Bismuth(III): Investigation of the Role of the Metal

摘要

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 activity against the promastigote form of Sb(III)-sensitive and -resistant Leishmania infantum chagasi and Leishmania amazonensis strains. Both complexes were more effective than dppz alone in inhibiting the growth of Leishmania promastigotes and were at least 77 and 2,400 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.