Screening of a PDE-focused library identifies imidazoles with in vitro and in vivo antischistosomal activity

Abstract

We report the evaluation of 265 compounds from a PDE-focused library for their antischistosomal activity, assessed in vitro using Schistosoma mansoni. Of the tested compounds, 171 (64%) displayed selective in vitro activity, with 16 causing worm hypermotility/spastic contractions and 41 inducing various degrees of worm killing at 100 μM, with the surviving worms displaying sluggish movement, worm unpairing and complete absence of eggs. The compounds that did not affect worm viability (n = 72) induced a complete cessation of ovipositing. 82% of the compounds had an impact on male worms whereas female worms were barely affected. In vivo evaluation in S. mansoni-infected mice with the in vitro ‘hit’ NPD-0274 at 20 mg/kg/day orally for 5 days resulted in worm burden reductions of 29% and intestinal tissue egg load reduction of 35% at 10 days post-treatment. Combination of praziquantel (PZQ) at 10 mg/kg/day for 5 days with NPD-0274 or NPD-0298 resulted in significantly higher worm killing than PZQ alone, as well as a reduction in intestinal tissue egg load, disappearance of immature eggs and an increase in the number of dead eggs.

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

“…Mature worm killing and ovipositing at 100 mM and 50 mM of new quinazolines (2-13) in comparison with previously reported data for NPD-1246 (1)14 . The final recording of worm killing was determined on day 5 (end of the observation period).…”

“…In a previous in vitro phenotypic screening campaign using Schistosoma mansoni with worm killing as primary outcome, compounds from a selected library were successfully classified and prioritised based on potency and selectivity 14 . The present work expands the evaluation of the antischistosomal activity for the quinazoline NPD-1246 ( 1 ) ( Figure 1 ) which was one of the best in vitro “hits”, involving (i) in vivo evaluation in the S. mansoni -infected mouse model, (ii) a medicinal chemistry programme to obtain better drug-like compounds and (iii) exploration of the putative target using computational consensus methodology applying ligand-based approaches.…”

Cloning and functional complementation of ten Schistosoma mansoni phosphodiesterases expressed in the mammalian host stages

“…We have recently published a first phenotypic screening of a PDE-inhibitor-enriched library and found that many of the compounds displayed anti-schistosomal effects such as worm survival, ovipositing and movement-with male worms being much more affected than female worms [34]. Several compounds were tested in mouse models of schistosomiasis and displayed partial clearance of worm and egg burdens.…”

“…Indeed, Caffrey and co-workers recently reported the cloning of several homologues of human PDE4 isoforms, and identified benzoxaborole inhibitors of these enzymes that induced hypermotility in the worms [33]. Moreover, the screening of a small library of potential PDE inhibitors identified numerous hits with activity on worm viability and/or ovipositing in vitro as well as reduced worm and egg burdens in a mouse model of S. mansoni infection [34].…”

“…Moreover, the screening of a small library of potential PDE inhibitors identified numerous hits with activity on worm viability and/or ovipositing in vitro as well as reduced worm and egg burdens in a mouse model of S . mansoni infection [ 34 ].…”