@article{192f66b43b784134b0a98544233b1825,
title = "Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni",
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, Schistosoma mansoni, Humans, Parasites, Animals, Anthelmintics/pharmacology, Brugia malayi, Nematospiroides dubius",
author = "Partridge, {Frederick A.} and Bataille, {Carole J.R.} and Ruth Forman and Marriott, {Amy E.} and Josephine Forde-Thomas and C{\'e}cile H{\"a}berli and Dinsdale, {Ria L.} and O'Sullivan, {James D.B.} and Willis, {Nicky J.} and Wynne, {Graham M.} and Helen Whiteland and John Archer and Andrew Steven and Jennifer Keiser and Turner, {Joseph D.} and Hoffmann, {Karl F.} and Taylor, {Mark J.} and Else, {Kathryn J.} and Russell, {Angela J.} and Sattelle, {David B.}",
note = "Funding Information: J.D.T., M.J.T., and A.E.M. were supported by a National Centre for Replacement, Refinement and Reduction of Animals in Research Studentship (NC3R Studentship NC/M00175 X/1) and a Bill and Melinda Gates Foundation award to the Liverpool School of Tropical Medicine (BMGF OPP1054324). F.A.P. and D.B.S. are supported by a Medical Research Council grant MR/N024842/1 and a UCL/Wellcome Trust Translational Partnership Pilot Grant. J.F.T., H.W., and K.F.H. acknowledge the Welsh Government Life Sciences Research Network Wales and the Wellcome Trust Pathfinder (201008/Z/16/Z) schemes for financial support of the Roboworm platform. We acknowledge the support of the University of Manchester FBMH EM facility (Tobias Starborg and David Smith), funding from the University of Manchester Facilitating Excellence Fund, and a Wellcome Trust equipment grant to the EM facility. R.F. is funded by MRC grant MR/N022661/1 awarded to K.J.E. Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",
year = "2021",
month = may,
day = "14",
doi = "10.1021/acsinfecdis.1c00025",
language = "English",
volume = "7",
pages = "1260--1274",
journal = "ACS Infectious Diseases",
issn = "2373-8227",
publisher = "American Chemical Society",
number = "5",
}
