Schistosoma mansoni Cathepsin B1: design and rational synthesis of new potential inhibitors

Abstract

Schistosomiasis is a neglected disease for which only one drug is available to the treatment, the praziquantel. Previous experience with other infectious diseases has shown that relying upon only one drug is a dangerous approach, even more, when it is frequently employed as prophylactics, as in the case of praziquantel. Consequently, the need for new pharmacological alternatives to treat Schistosomiasis is urgent. This project aims to associate different drug design strategies in the search for new S. mansoni Cathepsin B1 inhibitors. This target is an essential enzyme to the helminth since it is the main digestive enzyme associated with worm nutrition. Virtual Screening (VS) studies are proposed, employing two different compound libraries. The first one will aim FDA approved drugs, associating the VS with drug repositioning, a strategy which may improve and fasten the discovery for new antischistosomal compounds. The second will search for compounds with not explored chemical structures and may provide new chemical insights in the antischistosomal field. In parallel, the synthesis of new molecules, which mixes N-acylhydrazones and Vinyl sulfones characteristics is proposed. To these, previous knowledge about S. mansoni Cathepsin B1 inhibitors (vinyl sulfones) and the Topliss methodology will guide the structures synthesis. Finally, enzymatic inhibition and in vitro and in vivo studies with the worm are planned to be developed in collaborative work with the research groups coordinated by Dr Josué de Moraes, from Universidade de Guarulhos, and by Dr Conor Caffrey, from the University of California in San Diego. (AU)