Complexes of different nitrogen donor heterocyclic ligands with SbCl_3 and PhSbCl_2 as potential antileishmanial agents against SbIII-sensitive and -resistant parasites

摘要

Novel trivalent antimony complexes with the nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy), 1,10- phenanthroline (phen) or dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq) have been synthesized by the reaction with SbCl_3 or PhSbCl_2. The crystal structures of [Sb(phen)Cl_3] and [PhSb(phen)Cl_2]CH_3COOH were determined and shown to adopt a distorted square pyramid geometrywith a five-coordinated Sb center. Surprisingly, all the complexes, the ligands and PhSbCl_2 showed very high antileishmanial activities, with IC_(50) in the nanomolar range against SbIII-sensitive and -resistant Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis strains. These compoundsweremuch more active against these Leishmania strains than the old trivalent drug potassium antimonyl tartrate. [PhSb(phen)Cl_2]CH_3COOH complex was found to be the most active compound and the lack of cross-resistance of PhSbCl_2 suggests that the transport pathways of this compound across the cell membrane differ from those responsible for the resistance of Leishmania to Sb(OH)_3. In the case of the complexes with PhSbCl_2, our data supports the model that both ligand and metal contributed to the overall activity of the complex. Furthermore, among the complexeswith SbCl_3, only bipy showed an improved activity upon complexation. Cytotoxicity evaluations of these compounds against murine peritoneal macrophages showed high selective indexes in the range of 7-70 for [Sb(phen)Cl_3], [Sb(bipy)Cl_3] and [Sb(dpq)Cl_3] complexes, being much more selective than potassiumantimonyl tartrate. In conclusion, this study presents a set of newantileishmanial agents including one of themost active Sb-based compounds ever reported,which can contribute to the development of new chemotherapeutic strategies against leishmaniasis including Sb-resistant cases.