Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode.
ChemMedChem
; 10(11): 1821-36, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26395087
ABSTRACT
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. 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. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T.â
brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T.â
brucei.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Trypanosoma brucei brucei
/
Aciltransferasas
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Inhibidores Enzimáticos
/
Bibliotecas de Moléculas Pequeñas
/
Descubrimiento de Drogas
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Reino Unido