Today around 200 million people worldwide are parasitized by several species of Schistosoma and in particular S. mansoni, and more than 200 000 people die every year from this neglected disease. Praziquantel (PZQ) is the only drug currently administered. The mechanism of action of this drug has not been elucidated; however, inhibition of calcium channels and inhibition of adenosine uptake have been suggested to be involved in PZQ activity. Since PZQ-resistant worms have been identified, the development of new anti-schistosomiasis drugs is urgently needed. Recently, several furoxans (1,2,5-oxadiazole 2-oxides) have been shown to be endowed with good activity against S. mansoni. The proposed mechanism of action consists in the inhibition of thioredoxin glutathione reductase (TGR), an essential enzyme for parasite redox balance, through nitrosylation of cysteine and/or selenocysteine residues of the protein. This reaction takes place as a consequence of the interaction of the compounds with the enzyme and subsequent NO release. On this basis we decided to conjugate PZQ and furoxan pharmacophores in a single molecule in order to obtain dual drugs exploiting antischistosomal properties through two different mechanisms of action. Through slight modifications of an inexpensive and straightforward synthesis, six novel PZQ derivatives were prepared, three of them bearing furoxan moieties with the remainder bearing the corresponding furazan (1,2,5-oxadiazole) moieties and devoid of NO-donor properties. All the compounds have been subjected to structural and pharmacological characterization for their activity against adult ex vivo worms and their capability to inhibit TGR activity. Moreover in vivo studies are in progress in order to evaluate whether the compounds are able to decrease worm burdens in infected mice.
Praziquantel analogues containing NO-donor furoxans and related furazans as agents active against Schistosoma mansoni.
VOTTERO, FRANCESCA;GUGLIELMO, Stefano;FRUTTERO, Roberta;GASCO, Alberto;CORTESE, DANIELA;
2011-01-01
Abstract
Today around 200 million people worldwide are parasitized by several species of Schistosoma and in particular S. mansoni, and more than 200 000 people die every year from this neglected disease. Praziquantel (PZQ) is the only drug currently administered. The mechanism of action of this drug has not been elucidated; however, inhibition of calcium channels and inhibition of adenosine uptake have been suggested to be involved in PZQ activity. Since PZQ-resistant worms have been identified, the development of new anti-schistosomiasis drugs is urgently needed. Recently, several furoxans (1,2,5-oxadiazole 2-oxides) have been shown to be endowed with good activity against S. mansoni. The proposed mechanism of action consists in the inhibition of thioredoxin glutathione reductase (TGR), an essential enzyme for parasite redox balance, through nitrosylation of cysteine and/or selenocysteine residues of the protein. This reaction takes place as a consequence of the interaction of the compounds with the enzyme and subsequent NO release. On this basis we decided to conjugate PZQ and furoxan pharmacophores in a single molecule in order to obtain dual drugs exploiting antischistosomal properties through two different mechanisms of action. Through slight modifications of an inexpensive and straightforward synthesis, six novel PZQ derivatives were prepared, three of them bearing furoxan moieties with the remainder bearing the corresponding furazan (1,2,5-oxadiazole) moieties and devoid of NO-donor properties. All the compounds have been subjected to structural and pharmacological characterization for their activity against adult ex vivo worms and their capability to inhibit TGR activity. Moreover in vivo studies are in progress in order to evaluate whether the compounds are able to decrease worm burdens in infected mice.
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