ANALOGHI NO-DONATORI DEL PRAZIQUANTEL A STRUTTURA FUROSSANICA E RELATIVI FURAZANI. NUOVI AGENTI ATTIVI CONTRO LO Schistosoma mansoni

Schistosomiasis, also known as Bilharzia, is a tropical disease caused by trematode parasites (Schistosoma). Today around 200 million people worldwide are parasitized by several species of Schistosoma and more than 200 000 people die every year for this neglected disease. Current treatment depends on a single agent, praziquantel, but as praziquantel-resistant worms have been found, the development of new anti-schistosomiasis drugs is urgently needed [1]. The mechanism of action of this drug has not been elucidated yet and there are only few theories: inhibition of calcium channels, inhibition of adenosine uptake, premature hatching of the schistosome eggs, or a combination of the three. Recently, several furoxans (1,2,5-oxadiazole 2-oxides) have been shown to be endowed with good activity against Schistosoma mansoni. The proposed mechanism of action consists in the inhibition of Thioredoxin Glutathione Reductase (TGR), an essential enzyme for the parasite redox balance, through nitrosation 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 the subsequent NO release [2]. On this basis we decided to conjugate PZQ and furoxan pharmacophores in a single molecule in order to obtain a dual drug exploiting antischistosomal properties through two different mechanisms of action. Through slight modifications of an inexpensive and straightforward synthesis[3], six novel PZQ derivatives were prepared, three of them bearing furoxan moieties and the remaining ones bearing the corresponding furazan (1,2,5-oxadiazole) moieties 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 of inhibiting TGR. After exposure to the compounds it was observed that in some treatments worm contraction appeared and phenotype changed. The contraction in the presence of hybrid compounds was similar to that seen in the presence of authentic praziquantel. Interestingly, upon removal of drugs, the parasites regained their normal morphology and some were able to survive for eight days, except for the furoxan-3-carbonitrile hybrid which killed all worms at 50 μM. In addition the hybrids bearing furoxan moieties showed interesting inhibition against TGR, better than one showed by furoxans alone. The results of this study confirmed the importance of pyrazinoisoquinoline ring for the activity against ex vivo worms and the utility of NO-donor moiety to inhibit TGR; it should be interesting to investigate the interaction of the hybrids with the enzymatic target.