Complexes of different nitrogen donor heterocyclic ligands with SbCl3 and PhSbCl2 as potential antileishmanial agents against Sb(III)-sensitive and -resistant parasites

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 3 COOH were determined and shown to adopt a distorted square pyramid geometry with 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 Sb III -sensitive and -resistant Leishmania infantum (syn. Leishmania chagasi ) and Leishmania amazonensis strains. These compounds were much more active against these Leishmania strains than the old trivalent drug potassium antimonyl tartrate. [PhSb(phen)Cl 2 ]CH 3 COOH 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 complexes with 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 potassium antimonyl tartrate. In conclusion, this study presents a set of new antileishmanial agents including one of the most active Sb-based compounds ever reported, which can contribute to the development of new chemotherapeutic strategies against leishmaniasis including Sb-resistant cases.