Schistosomiasis is a parasitic flatworm infection with only one drug therapy currently on the market, praziquantel. A benzodiazepine, mechlonazepam displayed anti-parasitic efficacy but was not pursued due to dose-limiting sedation in human clinical trials. Our target is to design and synthesize new helminth druggable targets and lead compounds with decreased sedation, using Schistosoma parasitic blood flukes as a model. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ’s anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazodiazepines that immobilize worms in vitro. One of these hits, imidazodiazepine (XHE-II-048) which disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000x) affinity for human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.

Non-sedating anti-schistosomal benzodiazepines causes disruption of the tegument of Schistosoma mansoni

ACS Fall 2021

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