Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR

Background Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). Methods In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure–activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results It was found that several new derivatives, including compounds 6a–6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a–6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeted on SjTGR

Background: Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Since the increasing drug-resistant to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as a potential anti-schistosomiasis reagent targeted to thioredoxin glutathione reductase (TGR). Methods: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild type Schistosoma japonicum TGR (wtSjTGR) to develop new leading compound for schistosomiasis. Thirty nine novel derivatives were prepared to test their activity to both two enzymes. The docking method was used to detect the bind sites between active molecule and SjTGR; The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. Results: It was founded that several new derivatives such as compounds 6a-6d, 9ab, 9bd, 9be have a better activity to rSjTGR-Sec or SWAP containing wtSjTGR than furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity to both two enzymes. In particular, compound 6d with trifluoromethyl on pyridine ring has been found to have much higher inhibition to both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method revealed the matching sites between 6d and Schistosoma japonicumi TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. Conclusion: The data obtained herein showed preliminarily that 6d with trifluoromethyl on pyridine ring could be a valuable leading compound for further study.

Synthesis of Oxadiazole-2-Oxide Derivatives as Potential Drug Candidates for Schistosomiasis Targeted on SjTGR

Background: Schistosomiasis is a chronic parasitic disease that affects the health of millions people worldwide. Developing new drugs to treat schistosomiasis is crucial because of the increasing drug resistant to praziquantel (PZQ), the main drug for schistosomiasis. Oxadiazole-2-oxides have been identified as a potential anti-schistosomiasis reagent targeted to thioredoxin glutathione reductase (TGR).Methods: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicumi TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild type Schistosoma japonicumi TGR (wtSjTGR) in order to develop new leading compound for schistosomasis. Thirty nine novel derivatives were prepared to test their activity to both rSjTGR-Sec and SWAP containing wtSjTGR. The docking method was used to detect the bind sites between active molecule and SjTGR; The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed.Results: It was founded that several new derivatives such as compounds 6a-6d, 9ab, 9bd, 9be have better activity to rSjTGR-Sec or SWAP containing wtSjTGR than furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity to both rSjTGR-Sec and SWAP containing wtSjTGR especially, compound 6d with trifluoromethyl on pyridine ring was found to have much higher inhibition to both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan (4µM to SWAP containing wtSjTGR and 5.87µM to rSjTGR-Sec). Additionally, the docking method revealed the matching sites between 6d and Schistosoma japonicumi TGR (SjTGR), which theoretically lends support to inhibitory activity of 6d. Conclusion: The data obtained herein showed preliminarily that 6d with trifluoromethyl on pyridine ring could be a valuable leading compound for further study.