TY - JOUR
T1 - In vitro metabolic profile and in vivo antischistosomal activity studies of (η6-praziquantel)Cr(CO)3 derivatives
AU - Patra, Malay
AU - Ingram, Katrin
AU - Leonidova, Anna
AU - Pierroz, Vanessa
AU - Ferrari, Stefano
AU - Robertson, Murray N.
AU - Todd, Matthew H.
AU - Keiser, Jennifer
AU - Gasser, Gilles
PY - 2013/11/27
Y1 - 2013/11/27
N2 - In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η6-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η6-PZQ)Cr(CO)3 derivatives (S, S p)-1, (R, Rp)-1, (S, Rp)-2, and (R, S p)-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).
AB - In vitro metabolic behavior was investigated for two chromium tricarbonyl derivatives of the antischistosomal drug praziquantel (PZQ) with the formula (η6-PZQ)Cr(CO)3 (1 and 2), by use of human liver microsomes. The metabolic profiles of the derivatives differ significantly. The optically pure (η6-PZQ)Cr(CO)3 derivatives (S, S p)-1, (R, Rp)-1, (S, Rp)-2, and (R, S p)-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).
UR - http://www.scopus.com/inward/record.url?scp=84889256318&partnerID=8YFLogxK
U2 - 10.1021/jm401287m
DO - 10.1021/jm401287m
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C2 - 24219617
AN - SCOPUS:84889256318
SN - 0022-2623
VL - 56
SP - 9192
EP - 9198
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 22
ER -