In vitro metabolic profile and in vivo antischistosomal activity studies of (η(6)-praziquantel)Cr(CO)3 derivatives.
In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η(6)-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η(6)-PZQ)Cr(CO)3 derivatives (S, Sp)-1, (R, Rp)-1, (S, Rp)-2, and (R, Sp)-2 were also prepared to assess the eudysmic ratios of 1 and 2 against Schistosoma mansoni in vitro. A strong enantioselective antischistosomal activity was observed. The R-enantiomers are highly active against adult schistosomes in vitro (IC50 0.08-0.13 μM), whereas both S-enantiomers lack activity. The in vivo activity of 1 and 2 was then studied in mice harboring a chronic S. mansoni infection. A single dose of 1 and 2 (400 mg/kg) resulted in low worm burden reductions of 24% and 29% (p > 0.05).
Institute of Inorganic Chemistry and §Institute of Molecular Cancer Research, University of Zurich , Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Malay
M
Patra
Katrin
K
Ingram
Anna
A
Leonidova
Vanessa
V
Pierroz
Stefano
S
Ferrari
Murray N
MN
Robertson
Matthew H
MH
Todd
Jennifer
J
Keiser
Gilles
G
Gasser
D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D055620:Optical Phenomena; D011223:Praziquantel / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects*; D013237:Stereoisomerism; D013379:Substrate Specificity
D000871:Anthelmintics; D011223:Praziquantel