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

Qingqing Guo,Dequn Sun,Wenjiao Zhao,Shu Li,Gongming Li,Huan Chen,Yang Hong,Chao Feng

doi:10.1186/s13071-021-04634-4

Abstract

BackgroundSchistosomiasis 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).MethodsIn 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.ResultsIt 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.ConclusionThe data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.Graphical

Highlights

Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide
R-PZQ was approved by the Food and Drug Administration (FDA) as an orphan drug in 2018, it is at risk of resistance, and there is still no alternative drug against the migratory juvenile and subadult worms [6,7,8,9]
Using furoxan as the leading compound, a series of novel esters and amine derivatives have been synthesized by modifying the cyano moiety into an ester or amine group and replacing phenyl moiety with its bioisosteres pyridine or substituted pyridine

Summary

Introduction

Schistosomiasis is a chronic parasitic disease that affects millions of people’s health worldwide. Schistosomiasis is caused by five species of the trematode. The most effective drug for the treatment of schistosomiasis is praziquantel (PZQ) (1), which has been used extensively since the 1980s [5] in the clinic without any backup drugs. R-PZQ was approved by the Food and Drug Administration (FDA) as an orphan drug in 2018, it is at risk of resistance, and there is still no alternative drug against the migratory juvenile and subadult worms [6,7,8,9]. There is an urgent need to look for potential reagents to discover novel alternatives to PZQ for the treatment of schistosomiasis

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Results

Conclusion