Water-Soluble Ruthenium (II) Chiral Heteroleptic Complexes with Amoebicidal in Vitro and in Vivo Activity

Three water-soluble Ru­(II) chiral heteroleptic coordination compounds [Ru­(en)­(pdto)]­Cl2 (1), [Ru­(gly)­(pdto)]Cl (2), and [Ru­(acac)­(pdto)]Cl (3), where pdto = 2,2′-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]­dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, hav...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2017-02, Vol.60 (3), p.899-912
Main Authors: Toledano-Magaña, Yanis, García-Ramos, Juan C, Torres-Gutiérrez, Carolina, Vázquez-Gasser, Cristina, Esquivel-Sánchez, José M, Flores-Alamo, Marcos, Ortiz-Frade, Luis, Galindo-Murillo, Rodrigo, Nequiz, Mario, Gudiño-Zayas, Marco, Laclette, Juan P, Carrero, Julio C, Ruiz-Azuara, Lena
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemistry
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Apoptosis - drug effects
Cells, Cultured
Cricetinae
Crystallography, X-Ray
Entamoeba histolytica - drug effects
Humans
Inhibitory Concentration 50
Liver Abscess, Amebic - drug therapy
Mice
Reactive Oxygen Species - metabolism
Ruthenium Compounds - chemistry
Ruthenium Compounds - pharmacology
Ruthenium Compounds - therapeutic use
Stereoisomerism
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Summary:Three water-soluble Ru­(II) chiral heteroleptic coordination compounds [Ru­(en)­(pdto)]­Cl2 (1), [Ru­(gly)­(pdto)]Cl (2), and [Ru­(acac)­(pdto)]Cl (3), where pdto = 2,2′-[1,2-ethanediylbis-(sulfanediyl-2,1-ethanediyl)]­dipyridine, en = ethylendiamine, gly = glycinate, and acac = acetylacetonate, have been synthezised and fully characterized. The crystal structures of compounds 1–3 are described. The IC50 values for compounds 1–3 are within nanomolar range (14, 12, and 6 nM, respectively). The cytotoxicity for human peripheral blood lymphocytes is extremely low (>100 μM). Selectivity indexes for Ru­(II) compounds are in the range 700–1300. Trophozoites exposed to Ru­(II) compounds die through an apoptotic pathway triggered by ROS production. The orally administration to infected mice induces a total elimination of the parasite charge in mice faeces 1–2-fold faster than metronidazole. Besides, all compounds inhibit the trophozoite proliferation in amoebic liver abscess induced in hamster. All our results lead us to propose these compounds as promising candidates as antiparasitic agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.6b00795