Synthesis and characterization of a pyridine-2-thiol N-oxide gold(I) complex with potent antiproliferative effect against Trypanosoma cruzi and Leishmania sp. insight into its mechanism of action.

Abstract

In the search for new therapeutic tools against parasitic diseases caused by the Kinetoplastids Leishmania spp. and Trypanosoma cruzi, a novel gold(I) triphenylphosphine complex with the bioactive coligand pyridine-2-thiol N-oxide (mpo) was synthesized and characterized by using analytical and conductometric measurements, electrospray ionization-mass spectrometry (ESI) and electronic, FTIR and (1)H and (31)P NMR spectroscopies. A dinuclear structure is suggested for the complex. At a 1 microM concentration the complex induced in vitro after 30 min a potent leishmanicidal effect (LD(50)) against promastigotes of Leishmania (L.) mexicana while on Leishmania (V.) braziliensis with the same concentration only a leishmanistatic effect (IC(75)) was observed 48 h after treatment. Similar differential susceptibilities were also found when testing the ligand mpo, but at a higher dose (5 microM). In addition, the compound showed growth inhibitory effect on Dm28c T. cruzi epimastigotes in culture (IC(50) 0.09 microM), being even more active than the anti-trypanosomal reference drug Nifurtimox (IC(50) 6 microM). DNA interaction studies showed that this biomolecule does not constitute a main target for the mpo complex currently tested. Instead, the significant potentiation of the antiproliferative effect against both Leishmania species and T. cruzi could be associated to the inhibition of NADH fumarate reductase, a kinetoplastid parasite-specific enzyme absent in the host. Furthermore, due to its low unspecific cytotoxicity on mammalian cells (J774 macrophages), the new gold complex showed a selective anti-parasite activity. It constitutes a promising new potent chemotherapeutic alternative to be evaluated in vivo in experimental models of leishmaniasis and Chagas disease.

• Authors: Marisol Vieites, Pablo Smircich, Lucía Guggeri, Edgar Marchán, Alicia Gómez-Barrio, Maribel Navarro, Beatriz Garat, Dinorah Gambino
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 103 Issue 10 Pg. 1300-6 (Oct 2009) ISSN: 1873-3344 [Electronic] United States
• PMID: 19361864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Protozoan Proteins
• Pyridines
• Thiones
• pyrithione
• Gold
• Oxidoreductases Acting on CH-CH Group Donors
• fumarate reductase (NADH)

Topics

• Animals
• Antiprotozoal Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Cell Proliferation (drug effects)
• Chagas Disease (drug therapy)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gold (chemistry, pharmacology)
• Humans
• Leishmania (growth & development)
• Leishmaniasis (drug therapy)
• Mice
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors)
• Protozoan Proteins (antagonists & inhibitors)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Thiones (chemical synthesis, chemistry, pharmacology)
• Trypanosoma cruzi (growth & development)