Metal compounds for the treatment of parasitic diseases.

Abstract

The cysteine proteases of the trypanosomatid parasitic protozoa have been validated as targets for chemotherapy of Chagas' disease and leishmaniasis. Metal complexes of gold, platinum, iridium, palladium, rhodium and osmium have been reported to have activity against a variety of trypanosomatids, but the molecular target of these compounds has not been defined. The activity of gold(III) and palladium(II) cyclometallated complexes, and oxorhenium(V) complexes against mammalian and parasitic cysteine proteases was investigated. All gold(III) complexes (1-6) inhibited cathepsin B with IC(50) values in the range of 0.2-1.4 microM. Of the six palladium compounds, aceto[2,6-bis[(butylthio-kappa S)methyl]phenyl-kappa C]-, (SP-4-3)-palladium(II) (11) was the most potent inhibitor of cathepsin B with an IC(50) of 0.4 microM. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC(50) of 0.009 microM. Six complexes were further tested against the parasite cysteine proteases, cruzain from T. cruzi, and cpB from L. major; the most potent inhibitors were the two rhenium complexes (2(1H)-pyridinethionato-kappa S(2))[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (15) and chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16). The compounds were also evaluated in assays for parasite growth. Two oxorhenium(V) compounds ((p-methoxyphenylthiolato-S)[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (14) and (methanethiolato)[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium (V) (18)) and the palladium compound 11 inhibited T. cruzi intracellular growth, and compound 11 inhibited promastigote growth in three Leishmania species. In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis.

• Authors: Simon P Fricker, Renee M Mosi, Beth R Cameron, Ian Baird, Youngbao Zhu, Virginia Anastassov, Jennifer Cox, Patricia S Doyle, Elizabeth Hansell, Gloria Lau, Jonathan Langille, Micki Olsen, Ling Qin, Renato Skerlj, Rebecca S Y Wong, Zefferino Santucci, James H McKerrow
• Journal: Journal of inorganic biochemistry (J Inorg Biochem) Vol. 102 Issue 10 Pg. 1839-45 (Oct 2008) ISSN: 1873-3344 [Electronic] United States
• PMID: 18684510 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cysteine Proteinase Inhibitors
• Inorganic Chemicals
• Metals
• Trypanocidal Agents
• Cysteine Endopeptidases
• Cathepsin B

Topics

• Animals
• Cathepsin B (antagonists & inhibitors, metabolism)
• Chagas Disease (drug therapy)
• Cysteine Endopeptidases (metabolism)
• Cysteine Proteinase Inhibitors (pharmacology, therapeutic use)
• Humans
• Inorganic Chemicals (chemistry, pharmacology)
• Leishmania (drug effects)
• Leishmaniasis (drug therapy)
• Metals (pharmacology, therapeutic use)
• Trypanocidal Agents (pharmacology, therapeutic use)
• Trypanosoma (drug effects)