Discovery of novel antischistosomal scaffolds from the open access Pandemic Response Box

BACKGROUND: Treatment and control of schistosomiasis rely on a single drug, praziquantel. New orally active antischistosomals featuring novel molecular scaffolds are urgently needed to prevent the emergence of resistance. METHODS: We screened 400 drug-like compounds contained in the open-access Pandemic Response Box (PRB) against newly transformed schistosomula (NTS) at a concentration of 10 microM scoring death, changes in motility, and morphological alterations. Compounds displaying an activity >/=66% at 72 h underwent testing against adult Schistosoma mansoni in vitro. Fast-acting (>/=66% at 24 h), nontoxic drugs focusing on late-stage and approved drugs were investigated in the patent S. mansoni mouse model. RESULTS: We identified 26 hits active against NTS, of which 17 elicited >/=66% activity against adult S. mansoni following 24 h of drug exposure. The highest activity against adult S. mansoni was observed with MMV1581558 (EC50 value of 0.18 +/- 0.01 microM) and nitazoxanide (0.47 +/- 0.07 microM). Of the five compounds tested in vivo, MMV1581558 and the approved drug ozanimod reduced average worm burden versus controls by 42 % and 36 %, respectively, after a single oral dose of 200 mg/kg bodyweight in mice harboring a chronic S. mansoni infection. CONCLUSION: MMV1581558 discovered from screening the PRB represents a novel antischistosomal scaffold with high in vitro antischistosomal activity amenable to chemical modification for drug development.