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

Partridge, Frederick A, Bataille, Carole JR, Forman, Ruth, Marriott, Amy, Forde-Thomas, Josephine, Häberli, Cécile, Dinsdale, Ria L, O’Sullivan, James DB, Willis, Nicky J, Wynne, Graham M, Whiteland, Helen, Archer, John, Steven, Andrew, Keiser, Jennifer, Turner, Joseph ORCID: https://orcid.org/0000-0002-2185-5476, Hoffmann, Karl F, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275, Else, Kathryn J, Russell, Angela J and Sattelle, David 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, Vol 7, Issue 5, pp. 1260-1274.

Preview

Text acsinfecdis.1c00025.pdf - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

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.

Item Type:	Article
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 253 Anthelmintics QX Parasitology > QX 20 Research (General) QX Parasitology > Helminths. Annelida > QX 200 Helminths QX Parasitology > Helminths. Annelida > QX 203 Nematoda WC Communicable Diseases > Tropical and Parasitic Diseases > WC 850 Nematode infections (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1021/acsinfecdis.1c00025
Depositing User:	Stacy Murtagh
Date Deposited:	10 May 2021 10:41
Last Modified:	04 Jun 2021 10:18
URI:	https://archive.lstmed.ac.uk/id/eprint/17156

Statistics

View details

Actions (login required)

Edit Item