Benzimidazole analogues active against adult Schistosoma mansoni: SAR analyses, In vivo efficacy in mice, and preliminary mechanistic studies as potential inhibitors of hemozoin formation

Abstract

For over three decades, praziquantel (PZQ) has been the mainstay chemotherapy for prevention and treatment of schistosomiasis. The excessive use of PZQ, coupled with the lack of advanced drug candidates in the current anti-schistosomiasis drug development pipeline, emphasizes the genuine need for new drugs. In the current work, we investigated the antischistosomal potential of a new series of compounds derived from the privileged benzimidazole scaffold, which exhibited low micromolar IC₅₀ potency in the range of 1.0 – 2.7 μM against S. mansoni adult worms, in vitro. However, representative compounds showed low in vivo activity. One compound (15) reduced worm burden by 51.9% but not significant. Furthermore, by invoking inhibition of hemozoin formation, an immutable drug target in Schistosoma adult worms, as a likely contributing mode of action, we observed that the most potent analogues were equally potent inhibitors of β-hematin (synthetic hemozoin) formation in a cell-free assay.