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*

*Awdur cyfatebol y gwaith hwn

Allbwn ymchwil: Cyfraniad at gyfnodolynErthygladolygiad gan gymheiriaid

7 Dyfyniadau(SciVal)
355 Wedi eu Llwytho i Lawr (Pure)

Crynodeb

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.

Iaith wreiddiolSaesneg
Tudalennau (o-i)1260-1274
Nifer y tudalennau15
CyfnodolynACS Infectious Diseases
Cyfrol7
Rhif cyhoeddi5
Dyddiad ar-lein cynnar02 Ebr 2021
Dynodwyr Gwrthrych Digidol (DOIs)
StatwsCyhoeddwyd - 14 Mai 2021

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Gweld gwybodaeth am bynciau ymchwil 'Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni'. Gyda’i gilydd, maen nhw’n ffurfio ôl bys unigryw.

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