In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η~6?Praziquantel)Cr(CO)_3 Derivatives

摘要

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, S_p)-1, (R, Rp)-1, (S, R_p)-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 (IC_(50) 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).