Metal compounds for the treatment of parasitic diseases.
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.
Fricker
Simon P
SP
Genzyme Corporation, 49 New York Avenue, P.O. Box 9322, Framingham, MA 01701-9322, USA. simon.fricker@genzyme.com
Mosi
Renee M
RM
Cameron
Beth R
BR
Baird
Ian
I
Zhu
Youngbao
Y
Anastassov
Virginia
V
Cox
Jennifer
J
Doyle
Patricia S
PS
Hansell
Elizabeth
E
Lau
Gloria
G
Langille
Jonathan
J
Olsen
Micki
M
Qin
Ling
L
Skerlj
Renato
R
Wong
Rebecca S Y
RS
Santucci
Zefferino
Z
McKerrow
James H
JH
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007287:Inorganic Chemicals / Q000737:chemistry / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy*; D008670:Metals / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014345:Trypanosoma / Q000187:drug effects*
D015853:Cysteine Proteinase Inhibitors; D007287:Inorganic Chemicals; D008670:Metals; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; D002401:Cathepsin B