In Vitro Metabolic Profile and in Vivo Antischistosomal Activity Studies of (η⁶-Praziquantel)Cr(CO)₃ Derivatives

Abstract

ABSTRACT. The in vitro metabolic behavior was investigated of two chromium tricarbonyl derivatives of the antischistosomal drug Praziquantel (PZQ) with the formula (η 6 -PZQ)Cr(CO) 3(1 and 2), using human liver microsomes. It could be demonstrated that the metabolic profiles of the derivatives differ significantly. The optically pure (η 6 -PZQ)Cr(CO) 3 derivatives, (S, Sp)-1,were also prepared to assess of the eudysmic ratios of 1 and 2 against S. mansoni. A strong enantioselective antischistosomal activity was observed. The Renantiomers 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 Schistosoma mansoni (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).

Metal Complexes and Medicine: A Successful Combination

“…Of note, as discussed in more detail in our recent articles, the amount of chromium used in our studies is far below the threshold of intrinsic toxicity of this metal. [11,34,35] The first biological results were found to be extremely promising. Both organometallic compounds were found to have a remarkable antischistosomal activity (0.25 µM for 1 and 0.27 µM for 2), comparable to the parent organic drug PZQ (0.1 µM).…”

“…[34] We could also show, using human liver microsomes, that their metabolic profile was, surprisingly, relatively different to PZQ and to one another (Scheme 2). [35] On one hand, 1 is primarily demetallated to PZQ or hydroxylated to cis-4-PZQ-OH. On the other hand, only minor demetallation and hydroxylation were observed for 2.…”

“…This metabolite is formed after cleavage of the cyclohexanoyl moiety. [35] Another important study that we undertook to gain more insight into the mode of action of these organometallic compounds was to assess if the enantiomers/diastereoisomers of compounds 1 and 2 had similar biological activity. Indeed, PZQ is given to infected persons as a racemic mixture although only one of its enantiomers ((R)-PZQ) has an antischistosomal activity in vitro.…”

“…For comparison purposes, PZQ reached a total worm burden reduction of 96% with the same dosage. [35] These relatively disappointing results could be explained by distribution problems or protein binding. [11,35] Another route that our group has been exploring to discover novel lead antischistosomal drug candidates is drug-repurposing.…”

“…[35] These relatively disappointing results could be explained by distribution problems or protein binding. [11,35] Another route that our group has been exploring to discover novel lead antischistosomal drug candidates is drug-repurposing. This strategy is based on the use of an already known and/or an approved drug to treat a (completely) different disease.…”