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SAR of 4-Alkoxybenzoic Acid Inhibitors of the Trypanosome Alternative Oxidase.
Meco-Navas, Alejandro; Ebiloma, Godwin U; Martín-Domínguez, Ana; Martínez-Benayas, Irene; Cueto-Díaz, Eduardo J; Alhejely, Amani Saud; Balogun, Emmanuel O; Saito, Machi; Matsui, Miho; Arai, Natsumi; Shiba, Tomoo; Harada, Shigeharu; de Koning, Harry P; Dardonville, Christophe.
Afiliación
  • Meco-Navas A; Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • Ebiloma GU; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
  • Martín-Domínguez A; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • Martínez-Benayas I; Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • Cueto-Díaz EJ; Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • Alhejely AS; Instituto de Química Médica, IQM-CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.
  • Balogun EO; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
  • Saito M; Department of Biochemistry, Ahmadu Bello University, Zaria 2222, Nigeria.
  • Matsui M; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • Arai N; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • Shiba T; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • Harada S; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • de Koning HP; Department of Applied Biology, Kyoto Institute of Technology, Kyoto 606-8585, Japan.
  • Dardonville C; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
ACS Med Chem Lett ; 9(9): 923-928, 2018 Sep 13.
Article en En | MEDLINE | ID: mdl-30258542
The SAR of 4-hydroxybenzaldehyde inhibitors of the trypanosome alternative oxidase (TAO), a critical enzyme for the respiration of bloodstream forms of trypanosomes, was investigated. Replacing the aldehyde group with a methyl ester resulted in a 10-fold increase in TAO inhibition and activity against T. brucei. Remarkably, two analogues containing the 2-hydroxy-6-methyl scaffold (9e and 16e) displayed single digit nanomolar TAO inhibition, which constitute the most potent 4-alkoxybenzoic acid derivatives described to date. 9e was 50-times more potent against TAO and 10-times more active against T. brucei compared to its benzaldehyde analogue 1. The farnesyl derivative 16e was as potent a TAO inhibitor as ascofuranone with IC50 = 3.1 nM. Similar to ascofuranone derivatives, the 2-hydroxy and 6-methyl groups seemed essential for low nanomolar TAO inhibition of acid derivatives, suggesting analogous binding interactions with the TAO active site.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: ACS Med Chem Lett Año: 2018 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos