Today around 200 million people world-wide are infected with schistosomiasis and more than 200 000 people die every year for this neglected disease. Praziquantel is the only drug currently administrated, but as praziquantel-resistant worms have been found, the development of new anti-schistosomiasis drugs is urgently needed. Recently, several oxadiazole oxides have been shown to have good activity against Schistosoma mansoni. However, the shortcomings of these compounds are limited aqueous solubility and rapid metabolic degradation. For this reason we thought that the incorporation of the praziquantel structure may increase the efficiency of drug delivery and stability. Six novel oxadiazole oxides hybrids with praziquantel were synthesized: three of them with furoxan and three with furazan moieties replacing the hexane ring of praziquantel. Only the praziquantel hybrid with the furoxan-3-carbonitrile moiety and the praziquantel hybrid with the furoxan-3-carboxamide had significant activity against adult, ex vivo worms. The in vitro approach consisted of overnight exposure of parasite cultures to five different concentrations of each compound, followed by eight-day culture in drug-free medium. After exposure to the compounds it was observed in some treatments that contraction and worm 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. The oxadiazole oxides are good inhibitors targeting thioredoxin glutathione reductase (TGR), which is considered to be an essential protein to schistosomes and a potential drug target. Therefore, we tested the inhibition of TGR activity by these compounds. The three furoxan hybrids were able to inhibit TGR at 50 μM. In the inhibitory mechanism of the furoxan moiety it is proposed that nitric oxide from furoxan produced on reaction with TGR reacts with cysteine and/or selenocysteine residues in the active site of TGR, leading to inactivation of the enzyme. Our data support this hypothesis. In future we will determine nitric oxide production from these compounds, the IC50 values of these compounds against TGR, and evaluate whether the most potent compounds can decrease worm burdens in infected mice.

Hybrid praziquantel-oxadiazole oxides with activity against Schistosoma mansoni.

CORTESE, DANIELA;GUGLIELMO, Stefano;FRUTTERO, Roberta;
2011-01-01

Abstract

Today around 200 million people world-wide are infected with schistosomiasis and more than 200 000 people die every year for this neglected disease. Praziquantel is the only drug currently administrated, but as praziquantel-resistant worms have been found, the development of new anti-schistosomiasis drugs is urgently needed. Recently, several oxadiazole oxides have been shown to have good activity against Schistosoma mansoni. However, the shortcomings of these compounds are limited aqueous solubility and rapid metabolic degradation. For this reason we thought that the incorporation of the praziquantel structure may increase the efficiency of drug delivery and stability. Six novel oxadiazole oxides hybrids with praziquantel were synthesized: three of them with furoxan and three with furazan moieties replacing the hexane ring of praziquantel. Only the praziquantel hybrid with the furoxan-3-carbonitrile moiety and the praziquantel hybrid with the furoxan-3-carboxamide had significant activity against adult, ex vivo worms. The in vitro approach consisted of overnight exposure of parasite cultures to five different concentrations of each compound, followed by eight-day culture in drug-free medium. After exposure to the compounds it was observed in some treatments that contraction and worm 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. The oxadiazole oxides are good inhibitors targeting thioredoxin glutathione reductase (TGR), which is considered to be an essential protein to schistosomes and a potential drug target. Therefore, we tested the inhibition of TGR activity by these compounds. The three furoxan hybrids were able to inhibit TGR at 50 μM. In the inhibitory mechanism of the furoxan moiety it is proposed that nitric oxide from furoxan produced on reaction with TGR reacts with cysteine and/or selenocysteine residues in the active site of TGR, leading to inactivation of the enzyme. Our data support this hypothesis. In future we will determine nitric oxide production from these compounds, the IC50 values of these compounds against TGR, and evaluate whether the most potent compounds can decrease worm burdens in infected mice.
2011
AMCOP 63
Saint Mary's College, Notre Dame, IN, United States
23-25 June 2011
AMCOP 63, June 23-25, 2011 Saint Mary’s College Notre Dame, Indiana
21
22
Daniela Cortese; Francesca Vottero; Stefano Guglielmo; Roberta Fruttero; Alberto Gasco; Latasha Day and David L. Williams.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/153628
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