Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.

Partridge, F.A., Murphy, E.A., Willis, N.J., Bataille, C.J., Forman, R., Heyer-Chauhan, N., Marinič, B., Sowood, D.J., Wynne, G.M., Else, K.J., Russell, A.J. and Sattelle, D.B. 2017. Dihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo. PLoS Neglected Tropical Diseases. 11 (2) e0005359. https://doi.org/10.1371/journal.pntd.0005359

TitleDihydrobenz[e][1,4]oxazepin-2(3H)-ones, a new anthelmintic chemotype immobilising whipworm and reducing infectivity in vivo.
TypeJournal article
AuthorsPartridge, F.A., Murphy, E.A., Willis, N.J., Bataille, C.J., Forman, R., Heyer-Chauhan, N., Marinič, B., Sowood, D.J., Wynne, G.M., Else, K.J., Russell, A.J. and Sattelle, D.B.
Abstract

Trichuris trichiura is a human parasitic whipworm infecting around 500 million people globally, damaging the physical growth and educational performance of those infected. Current drug treatment options are limited and lack efficacy against the worm, preventing an eradication programme. It is therefore important to develop new treatments for trichuriasis. Using Trichuris muris, an established model for T. trichiura, we screened a library of 480 novel drug-like small molecules for compounds causing paralysis of the ex vivo adult parasite. We identified a class of dihydrobenz[e][1,4]oxazepin-2(3H)-one compounds with anthelmintic activity against T. muris. Further screening of structurally related compounds and resynthesis of the most potent molecules led to the identification of 20 active dihydrobenzoxazepinones, a class of molecule not previously implicated in nematode control. The most active immobilise adult T. muris with EC50 values around 25–50μM, comparable to the existing anthelmintic levamisole. The best compounds from this chemotype show low cytotoxicity against murine gut epithelial cells, demonstrating selectivity for the parasite. Developing a novel oral pharmaceutical treatment for a neglected disease and deploying it via mass drug administration is challenging. Interestingly, the dihydrobenzoxazepinone OX02983 reduces the ability of embryonated T. muris eggs to establish infection in the mouse host in vivo. Complementing the potential development of dihydrobenzoxazepinones as an oral anthelmintic, this supports an alternative strategy of developing a therapeutic that acts in the environment, perhaps via a spray, to interrupt the parasite lifecycle. Together these results show that the dihydrobenzoxazepinones are a new class of anthelmintic, active against both egg and adult stages of Trichuris parasites. They demonstrate encouraging selectivity for the parasite, and importantly show considerable scope for further optimisation to improve potency and pharmacokinetic properties with the aim of developing a clinical agent.

Article numbere0005359
JournalPLoS Neglected Tropical Diseases
Journal citation11 (2)
ISSN1935-2735
Year2017
PublisherPublic Library of Science
Publisher's version
License
CC BY 4.0
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1371/journal.pntd.0005359
PubMed ID28182663
Web address (URL)http://europepmc.org/abstract/med/28182663
Publication dates
Published09 Feb 2017

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