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

Abstract

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.