The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad-spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) is not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index and point to the C3 position of the benzodiazepine ring system as a logical site for further structure–activity exploration to further optimize this chemical series.
Development of non-sedating benzodiazepines with in vivo antischistosomal activity | Antimicrobial Agents and Chemotherapy
While the neglected tropical disease schistosomiasis infects over 200 million people worldwide (1), control of the disease is almost entirely reliant on one drug, praziquantel (PZQ). A recent meta-analysis of PZQ efficacy over four decades indicates cure rates between 57% and 88% (2), but there is the concern that resistance may emerge with repeated rounds of mass drug administration (3). Parasite resistance can be selected in the laboratory (4–6), and there are numerous reports of treatment failure in the field (7, 8). An alternative antischistosomal drug would be of obvious use in the event of either PZQ treatment failure or resistance. However, older antischistosomal chemotherapies tend to either have unacceptable toxicity (e.g., antimony compounds) or lack broad efficacy against the two species of schistosomes infecting humans in Africa [e.g., oxamniquine is only effective against Schistosoma mansoni (9), and metrifonate is only effective against Schistosoma haematobium (10)]. Benzodiazepines are promising antischistosomal candidates because they are effective against both of these African species (11, 12). Binding and functional assays indicate that meclonazepam (MCLZ) and PZQ do not appear to act on the same target (13, 14). Additionally, unlike PZQ, MCLZ can cure schistosomiasis at the juvenile, liver stage of parasite infections (11, 15).
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