Deciphering the enzymatic target of a new family of antischistosomal agents bearing a quinazoline scaffold using complementary computational tools

Victor Sebastian-Perez,Alfonso García-Rubia,Sayed H Seif El-Din,Abdel-Nasser A Sabra,Naglaa M El-Lakkany,Samia William,Tom L Blundell,Louis Maes,Ana Martinez,Nuria E Campillo,Sanaa S Botros,Carmen Gil

doi:10.1080/14756366.2020.1712595

Abstract

A previous phenotypic screening campaign led to the identification of a quinazoline derivative with promising in vitro activity against Schistosoma mansoni. Follow-up studies of the antischistosomal potential of this candidate are presented here. The in vivo studies in a S. mansoni mouse model show a significant reduction of total worms and a complete disappearance of immature eggs when administered concomitantly with praziquantel in comparison with the administration of praziquantel alone. This fact is of utmost importance because eggs are responsible for the pathology and transmission of the disease. Subsequently, the chemical optimisation of the structure in order to improve the metabolic stability of the parent compound was carried out leading to derivatives with improved drug-like properties. Additionally, the putative target of this new class of antischistosomal compounds was envisaged by using computational tools and the binding mode to the target enzyme, aldose reductase, was proposed.

Highlights

Schistosomiasis is a parasitic infectious disease caused by a trematode belonging to Schistosoma spp
The results indicate that the compound becomes extensively metabolised through phase-I but not through phase-II metabolism
The compound was extensively metabolised through phase-I metabolism (Table 1)

Summary

Introduction

Schistosomiasis is a parasitic infectious disease caused by a trematode belonging to Schistosoma spp. Part of the eggs is passed in the faeces or urine to continue the parasite’s life cycle by contaminating water while most become trapped in body tissues causing immune-inflammatory responses and progressive damage to organs[1]. This neglected tropical disease is endemic in a number of tropical and subtropical countries representing a serious health problem especially in poor communities. The disease has recently reached Europe, demonstrating the possibility to emerge in new geographical areas previously unknown related to migration movements and parasite genetic variants[2]

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Conclusion