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

Partridge, F.A., Bataille, C.J.R., Forman, R., Marriott, A.E., Forde-Thomas, J., Häberli, C., Dinsdale, R.L., O’Sullivan, J.D.B., Willis, N.J., Wynne, G.M., Whiteland, H., Archer, J., Steven, A., Keiser, J., Turner, J.D., Hoffmann, K.F., Taylor, M.J., Else, K.J., Russell, A.J. and Sattelle, D.B. 2021. Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni. ACS Infectious Diseases. 7 (5), pp. 1260-1274. https://doi.org/10.1021/acsinfecdis.1c00025

TitleStructural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni
TypeJournal article
AuthorsPartridge, F.A., Bataille, C.J.R., Forman, R., Marriott, A.E., Forde-Thomas, J., Häberli, C., Dinsdale, R.L., O’Sullivan, J.D.B., Willis, N.J., Wynne, G.M., Whiteland, H., Archer, J., Steven, A., Keiser, J., Turner, J.D., Hoffmann, K.F., Taylor, M.J., Else, K.J., Russell, A.J. and Sattelle, D.B.
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.

JournalACS Infectious Diseases
Journal citation7 (5), pp. 1260-1274
ISSN2373-8227
Year2021
PublisherACS Publications
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1021/acsinfecdis.1c00025
Web address (URL)https://doi.org/10.1021/acsinfecdis.1c00025
Publication dates
Published02 Apr 2021

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