Abstract
BackgroundSchistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. Although PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. A hybrid drug containing different pharmacophores within a single molecule is a promising strategy. Our earlier in vivo studies showed the significant antiparasitic activity of a praziquantel derivative, DW-3-15, against Schistosoma japonicum. In the present study, DW-3-15 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro. An in vivo study was conducted to assess the effect of commercial DW-3-15 on worm burden, egg production and diameter of granulomas. Additionally, to gain insight into the mechanism of action for DW-3-15, morphological changes in the tegument of S. japonicum were also examined.ResultsThe in vitro study showed the antiparasitic activity of DW-3-15 against S. japonicum, with significant reductions in viability of adult and juvenile worms, worm pairings and egg output. Compared to PZQ, DW-3-15 induced similar ultrastructural changes and evident destruction of the tegument surface in male worms. In vivo, the oral administration of DW-3-15 at a dose of 400 mg/kg per day for five consecutive days in mice significantly reduced the total worm burden and number of eggs in the liver. Histological analysis of the livers showed a marked reduction in the average diameter of the egg granuloma.ConclusionsOur findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide.
Highlights
Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world
DW‐3‐15 alters the viability of adult and juvenile worms in vitro DW-3-15 was tested at concentrations of 2.5, 5 and 10 μM, but no significant worm mortality was observed in the pre-experiment
DW‐3‐15 reduces worm burden and egg formation in vivo After observing the potent antischistosomal activity of DW-3-15 in vitro, we further evaluated its effect on adult worms in vivo
Summary
Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. DW-315 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro. For the past 40 years, praziquantel (PZQ), which can treat all species of schistosomiasis, has been the only recommended drug for this devastating disease. Considering the high failure rate of these candidate compounds during preclinical and clinical trials, the development of alternative drugs requires further significant investment of time and resources
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