Human African trypanosomiasis (HAT), or African sleeping sickness, is endemic in sub-Saharan Africa, claiming the lives of about 10 000 people every year. Further work is required to increase selectivity over the human NMT isoform and activity against T. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. The benzomorpholinone was also found to bind in a similar region. This provides potential for further optimisation. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis.
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