title: Complexes of different nitrogen donor heterocyclic ligands with SbCl3 and PhSbCl2 as potential antileishmanial agents against Sb(III)-sensitive and -resistant parasites.
abstract: 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 SbCl3 or PhSbCl2. The crystal structures of [Sb(phen)Cl3] and [PhSb(phen)Cl2]CH3COOH were determined and shown to adopt a distorted square pyramid geometry with a five-coordinated Sb center. Surprisingly, all the complexes, the ligands and PhSbCl2 showed very high antileishmanial activities, with IC50 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)Cl2]CH3COOH complex was found to be the most active compound and the lack of cross-resistance of PhSbCl2 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 PhSbCl2, our data supports the model that both ligand and metal contributed to the overall activity of the complex. Furthermore, among the complexes with SbCl3, 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)Cl3], [Sb(bipy)Cl3] and [Sb(dpq)Cl3] 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.
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Edgar H
authors.initials: EH
authors.lastname: Lizarazo-Jaimes
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Priscila G
authors.initials: PG
authors.lastname: Reis
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Filipe M
authors.initials: FM
authors.lastname: Bezerra
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Bernardo L
authors.initials: BL
authors.lastname: Rodrigues
authors.affiliation: Infectious Disease Research Centre, Laval University, 2705 Boulevard Laurier, RC-709, G1V 4G2 Québec, QC, Canada.
authors.forename: Rubens L
authors.initials: RL
authors.lastname: Monte-Neto
authors.affiliation: Department of Parasitology, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Maria N
authors.initials: MN
authors.lastname: Melo
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Frézard
authors.affiliation: Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais (UFMG), Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. Electronic address: demichel@netuno.lcc.ufmg.br.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Demicheli
mesh_terms: D000818:Animals; D000965:Antimony / Q000737:chemistry / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004352:Drug Resistance, Microbial; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009584:Nitrogen / Q000737:chemistry*; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D006571:Heterocyclic Compounds; D010618:Phenanthrolines; D000965:Antimony; D009584:Nitrogen; C025205:1,10-phenanthroline
keywords: 1,10-Phenanthroline; 2,2′-Bipyridine; Antileishmanial; Antimony; Dipyridoquinoxaline; Leishmania