Smith, Alasdair; Wall, Richard J; Patterson, Stephen; Rowan, Tim; Rico Vidal, Eva; Stojanovski, Laste; Huggett, Margaret; Hampton, Shahienaz E; Thomas, Michael G; Corpas Lopez, Victoriano; +19 more... Gillingwater, Kirsten; Duke, Jeff; Napier, Grant; Peter, Rose; Vitouley, Hervé S; Harrison, Justin R; Milne, Rachel; Jeacock, Laura; Baker, Nicola; Davis, Susan H; Simeons, Frederick; Riley, Jennifer; Horn, David; Brun, Reto; Zuccotto, Fabio; Witty, Michael J; Wyllie, Susan; Read, Kevin D; Gilbert, Ian H; (2022) Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis. Journal of medicinal chemistry, 65 (7). pp. 5606-5624. ISSN 0022-2623 DOI: https://doi.org/10.1021/acs.jmedchem.1c02104
Permanent Identifier
Use this Digital Object Identifier when citing or linking to this resource.
Abstract
African animal trypanosomiasis or nagana, caused principally by infection of the protozoan parasites Trypanosoma congolense and Trypanosoma vivax, is a major problem in cattle and other livestocks in sub-Saharan Africa. Current treatments are threatened by the emergence of drug resistance and there is an urgent need for new, effective drugs. Here, we report the repositioning of a compound series initially developed for the treatment of human African trypanosomiasis. A medicinal chemistry program, focused on deriving more soluble analogues, led to development of a lead compound capable of curing cattle infected with both T. congolense and T. vivax via intravenous dosing. Further optimization has the potential to yield a single-dose intramuscular treatment for this disease. Comprehensive mode of action studies revealed that the molecular target of this promising compound and related analogues is the cyclin-dependent kinase CRK12.
Item Type | Article |
---|---|
Faculty and Department | Faculty of Infectious and Tropical Diseases > Department of Infection Biology |
PubMed ID | 35303411 |
Elements ID | 196339 |
Official URL | http://dx.doi.org/10.1021/acs.jmedchem.1c02104 |
Download
Filename: Smith_etal_2022_Repositioning-of-a-diaminothiazole-series.pdf
Licence: Creative Commons: Attribution 4.0
Download