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

Authors Organisations
  • Frederick A. Partridge(Author)
    University College London
  • Carole J.R. Bataille(Author)
    University of Oxford
  • Ruth Forman(Author)
    Faculty of Biology, Medicine and Health
  • Amy E. Marriott(Author)
    Liverpool School of Tropical Medicine
  • Josephine Forde-Thomas(Author)
  • Cécile Häberli(Author)
    Swiss Tropical Institute
    University of Basel
  • Ria L. Dinsdale(Author)
    University of Oxford
  • James D.B. O'Sullivan(Author)
    Faculty of Biology, Medicine and Health
    The University of Manchester
  • Nicky J. Willis(Author)
    University of Oxford
    University College London
  • Graham M. Wynne(Author)
    University of Oxford
  • Helen Whiteland(Author)
  • John Archer(Author)
    Liverpool School of Tropical Medicine
  • Andrew Steven(Author)
    Liverpool School of Tropical Medicine
  • Jennifer Keiser(Author)
    Swiss Tropical Institute
    University of Basel
  • Joseph D. Turner(Author)
    Liverpool School of Tropical Medicine
  • Karl Hoffmann(Author)
  • Mark J. Taylor(Author)
    Liverpool School of Tropical Medicine
  • Kathryn J. Else(Author)
    Faculty of Biology, Medicine and Health
  • Angela J. Russell(Author)
    University of Oxford
  • David B. Sattelle(Author)
    University College London
Type Article
Original languageEnglish
Pages (from-to)1260-1274
Number of pages15
JournalACS Infectious Diseases
Volume7
Issue number5
Early online date02 Apr 2021
DOI
Publication statusPublished - 14 May 2021
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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.

Keywords

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

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