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.