Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni.

Frederick A Partridge,John Archer,Andrew Steven,Helen Whiteland,Cécile Häberli,David B Sattelle,Ruth Forman,Angela J Russell,Jennifer Keiser,Josephine Forde-Thomas,Joseph D Turner,Karl F Hoffmann,Mark J Taylor,Nicky J Willis,Graham M Wynne,Kathryn J Else,James D B O'sullivan ,Carole J R Bataille ,Ria L Dinsdale ,Amy E Marriott

doi:10.1021/acsinfecdis.1c00025

Abstract

Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here, we report a systematic investigation of the structure–activity relationship of the anthelmintic activity of DHB compounds. We synthesized 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQs) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.

Highlights

Nine hundred million people are infected with the soiltransmitted helminths Ascaris lumbricoides, hookworm, and Trichuris trichiura
We previously described a hit series of five dihydrobenz[e][1,4]oxazepin-2(3H)-one (DHB) compounds with anthelmintic activity against ex vivo T. muris.[21]
We extend our investigations of the activity of the DHB compounds against Brugia malayi, a causative agent of lymphatic filariasis, Heligmosomoides polygyrus bakeri, a mouse gastrointestinal nematode model, and the human blood fluke, Schistosoma mansoni

Summary

Introduction

Nine hundred million people are infected with the soiltransmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). Low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from trichuriasis. We demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics. The current mass drug administration protocol may not be able to break transmission and reduce the prevalence of moderate to heavy whipworm infections to below 2% as required to eliminate morbidity.[3] Due to the poor single dose efficacy of the benzimidazole drugs against whipworm, there have been extensive efforts to identify more efficacious drug combina-. Polymorphisms in the betatubulin gene that are associated with benzimidazole resistance are found in populations of human whipworm, and the frequency of these polymorphisms increased after albendazole treatment.[12,13]

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