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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
403 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1260-1274
Number of pages15
JournalACS Infectious Diseases
Volume7
Issue number5
Early online date02 Apr 2021
DOIs
Publication statusPublished - 14 May 2021

Keywords

  • anthelmintic
  • drug discovery
  • nematode
  • trematode
  • Trichuris
  • whipworm

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