Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)

Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-flu...

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Detalles Bibliográficos
Autores principales: Akama, Tsutomu, Zhang, Yong-Kang, Freund, Yvonne R., Berry, Pamela, Lee, Joanne, Easom, Eric E., Jacobs, Robert T., Plattner, Jacob J., Witty, Michael J., Peter, Rosemary, Rowan, Tim G., Gillingwater, Kirsten, Brun, Reto, Nare, Bakela, Mercer, Luke, Xu, Musheng, Wang, Jiangong, Liang, Hao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science Ltd 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5720837/
https://www.ncbi.nlm.nih.gov/pubmed/29169674
http://dx.doi.org/10.1016/j.bmcl.2017.11.028
Descripción
Sumario:Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC(50) values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.

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