1. Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni
- Author
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Helen Whiteland, James O'Sullivan, Karl F. Hoffmann, Josephine Forde-Thomas, Carole J. R. Bataille, Nicky J. Willis, Kathryn J. Else, David B. Sattelle, Frederick A. Partridge, Mark J. Taylor, Cécile Häberli, Andrew Steven, John Archer, Graham Michael Wynne, Jennifer Keiser, Joseph D. Turner, Angela J. Russell, Ruth Forman, Amy E Marriott, and Ria L Dinsdale
- Subjects
0301 basic medicine ,Trichuris ,Trichuriasis ,nematode ,030106 microbiology ,030231 tropical medicine ,Brugia malayi ,Trichuris muris ,Article ,Microbiology ,drug discovery ,trematode ,03 medical and health sciences ,0302 clinical medicine ,qx_200 ,parasitic diseases ,medicine ,qx_203 ,Animals ,Humans ,Parasites ,Anthelmintic ,030304 developmental biology ,Anthelmintics ,0303 health sciences ,Nematospiroides dubius ,biology ,anthelmintic ,whipworm ,qv_253 ,Schistosoma mansoni ,medicine.disease ,biology.organism_classification ,wc_850 ,3. Good health ,030104 developmental biology ,Infectious Diseases ,qx_20 ,Trichuris trichiura ,Heligmosomoides polygyrus ,Ascaris lumbricoides ,medicine.drug - 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 synthesised 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 (DBQ) 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.Author summaryAround a billion people are infected by the soil transmitted helminths Ascaris, hookworm and whipworm. In the case of whipworm, the benzimidazole drugs, which are distributed to school children in affected areas, have low cure rates. This means that finding an improved treatment for whipworm is a priority. We previously identified five DHB compounds in a screen for new compounds active against whipworm. Here we systematically dissect these molecules, making 47 modified versions of the compounds. This allowed us to define the features of these compounds that are important for activity against whipworm. We also demonstrate activity of DHB compounds against other parasitic nematodes, and against Schistosoma mansoni, a trematode parasite. These results show the potential for further development of DHB compounds as broad-spectrum anthelmintics.
- Published
- 2021