Abstract
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.
Highlights
Pentavalent antimonials such as sodium stibogluconate and meglumine antimonate, have been used in the treatment of all forms of leishmaniasis for more than half a century [1,2]
The corresponding 1H-NMR spectra showed only one set of signals, shifted downfield in both complexes with respect to the free ligand (Table 1). 1H-NMR spectra of [Sb(dppz)Cl3] and [Bi(dppz)Cl3] complexes in dimethyl sulfoxide-d6 (DMSO-d6) exhibited the presence of the polypyridine ligand aromatic protons between δ 9.68 and 8.05 ppm
All the preparations were done under anhydrous conditions. dppz was synthesized by a condensation of 1,10-phenanthroline-5,6-dione and ortho-phenylenediamine according to the procedure described by Liang [37]
Summary
Pentavalent antimonials such as sodium stibogluconate and meglumine antimonate, have been used in the treatment of all forms of leishmaniasis for more than half a century [1,2]. Its localization in intracellular vesicle membranes suggests that it sequesters Sb(III)-thiol complexes into these vesicles [7] Other mechanisms such as a diminished biological reduction of Sb(V) to Sb(III) [8], the loss of an aquaglyceroporin (AQP1) allele or its down regulation [9] and hypoxic conditions [10] have been reported to cause an increase in resistance to pentavalent antimonials. In this context, there is a great need for new safe and effective drugs that do not exhibit cross-resistance with conventional antimonial drugs. The present paper reports for the first time a new experimental approach, based on tests against metal-resistant mutants and their respective parental sensitive strains, to get insight into the role of the metal in the cytotoxicity of a metal complex
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
