Novel minor groove binders cure animal African trypanosomiasis in an in vivo mouse model

Giordani, F. , Khalaf, A. I., Gillingwater, K., Munday, J. C. , de Koning, H. P. , Suckling, C. J., Barrett, M. P. and Scott, F. J. (2019) Novel minor groove binders cure animal African trypanosomiasis in an in vivo mouse model. Journal of Medicinal Chemistry, 62(6), pp. 3021-3035. (doi: 10.1021/acs.jmedchem.8b01847) (PMID:30763102)

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Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa due to its huge impact on livestock health. Existing therapies including those based upon Minor Groove Binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places due to the emergence of resistant parasites. Consequently, the need for new chemotherapies is urgent. Here, we describe a structurally distinct class of MGBs, Strathclyde MGBs (S-MGBs), which display excellent in vitro activities against the principal causative organisms of AAT, Trypanosoma congolense and T. vivax. We also show the cure of T. congolense-infected mice by a number of these compounds. In particular, we identify S-MGB-234, compound 7, as curative using 2 applications of 50 mg/kg intraperitoneally. Crucially, we demonstrate that S-MGBs do not show cross-resistance with the current diamidine drugs and are not internalised via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for animal African trypanosomiasis.

Item Type:Articles
Additional Information:Funding was provided by BBSRC grant BB/N007638/1. A correction to this article is available at
Glasgow Author(s) Enlighten ID:Khalaf, Dr Abedawn and Munday, Dr Jane and De Koning, Professor Harry and Giordani, Dr Federica and Barrett, Professor Michael
Authors: Giordani, F., Khalaf, A. I., Gillingwater, K., Munday, J. C., de Koning, H. P., Suckling, C. J., Barrett, M. P., and Scott, F. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Science and Engineering > School of Chemistry
Journal Name:Journal of Medicinal Chemistry
Publisher:American Chemical Society
ISSN (Online):1520-4804
Published Online:14 February 2019
Copyright Holders:Copyright © 2019 American Chemical Society
First Published:First published in Journal of Medicinal Chemistry 62(6):3021-3035
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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