English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/167649
COMPARTIR / IMPACTO:
Estadísticas
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:
Título

Inhibition of trypanosome alternative oxidase without its N-terminal mitochondrial targeting signal (ΔMTS-TAO) by cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde derivatives active against T. brucei and T. congolense

AutorEbiloma, Godwin U.; Díaz, Teresa; Balogun, Emmanuel O.; Abad, Lucía; Donachie, Anne; Kaiser, Marcel; Herraiz Tomico, Tomás ; Inaoka, Daniel K.; Shiba, Tomoo; Harada, Shigeharu; Kita, Kiyoshi; Koning, Harry P. de; Dardonville, Christophe
Palabras claveParasite respiration
SHAM
Triphenylphosphonium salt (TPP)
Quinolinium salt
Lipophilic cation
Trypanosomiasis
Trypanocide
Mitochondrial targeting
Trypanosome alternative oxidase (TAO)
Trypanosoma brucei
T. congolense
T. b. rhodesiense
Fecha de publicación2018
EditorElsevier
CitaciónEuropean Journal of Medicinal Chemistry 150: 385-402 (2018)
ResumenAfrican trypanosomiasis is a neglected parasitic disease that is still of great public health relevance, and a severe impediment to agriculture in endemic areas. The pathogens possess certain unique metabolic features that can be exploited for the development of new drugs. Notably, they rely on an essential, mitochondrially-localized enzyme, Trypanosome Alternative Oxidase (TAO) for their energy metabolism, which is absent in the mammalian hosts and therefore an attractive target for the design of safe drugs. In this study, we cloned, expressed and purified the physiologically relevant form of TAO, which lacks the N-terminal 25 amino acid mitochondrial targeting sequence (ΔMTS-TAO). A new class of 32 cationic and non-cationic 4-hydroxybenzoate and 4-alkoxybenzaldehyde inhibitors was designed and synthesized, enabling the first structure-activity relationship studies on ΔMTS-TAO. Remarkably, we obtained compounds with enzyme inhibition values (IC) as low as 2 nM, which were efficacious against wild type and multidrug-resistant strains of T. brucei and T. congolense. The inhibitors 13, 15, 16, 19, and 30, designed with a mitochondrion-targeting lipophilic cation tail, displayed trypanocidal potencies comparable to the reference drugs pentamidine and diminazene, and showed no cross-resistance with the critical diamidine and melaminophenyl arsenical classes of trypanocides. The cationic inhibitors 15, 16, 19, 20, and 30 were also much more selective (900 - 344,000) over human cells than the non-targeted neutral derivatives (selectivity >8-fold). A preliminary in vivo study showed that modest doses of 15 and 16 reduced parasitaemia of mice infected with T. b. rhodesiense (STIB900). These compounds represent a promising new class of potent and selective hits against African trypanosomes.
Versión del editorhttp://dx.doi.org/10.1016/j.ejmech.2018.02.075
URIhttp://hdl.handle.net/10261/167649
Identificadoresdoi: 10.1016/j.ejmech.2018.02.075
issn: 0223-5234
e-issn: 768-3254
Aparece en las colecciones: (ICTAN) Artículos
(IQM) Artículos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
accesoRestringido.pdf15,38 kBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 

Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.