Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model.

Giordani F; Khalaf AI; Gillingwater K; Munday JC; de Koning HP; Suckling CJ; Barrett MP; Scott FJ

doi:10.1021/acs.jmedchem.8b01847

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Journal article

Novel Minor Groove Binders Cure Animal African Trypanosomiasis in an in Vivo Mouse Model.

Giordani F Department of Pure and Applied Chemistry, WestCHEM , University of Strathclyde , Glasgow G1 1XL , U.K.
Khalaf AI Parasite Chemotherapy, Department of Medical Parasitology and Infection Biology , Swiss Tropical and Public Health Institute , Basel 4051 , Switzerland.
Gillingwater K Department of Pure and Applied Chemistry, WestCHEM , University of Strathclyde , Glasgow G1 1XL , U.K.
Munday JC Glasgow Polyomics , University of Glasgow , Glasgow G61 1QH , U.K.
de Koning HP Department of Biological and Geographical Sciences, School of Applied Sciences , University of Huddersfield , Huddersfield HD1 3DH , U.K.
Suckling CJ
Barrett MP
Scott FJ

2019-02-15

Published in:

Journal of medicinal chemistry. - 2019

Structure-Activity Relationship

English Animal African trypanosomiasis (AAT) is a significant socioeconomic burden for sub-Saharan Africa because of its huge impact on livestock health. Existing therapies including those based on minor groove binders (MGBs), such as the diamidines, which have been used for decades, have now lost efficacy in some places because of 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 Trypanosoma 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 by using two 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 internalized via the transporters used by diamidines. This study demonstrates that S-MGBs have significant potential as novel therapeutic agents for AAT.

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