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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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
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author 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
author_facet 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
author_sort Akama, Tsutomu
collection PubMed
description 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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spelling pubmed-57208372018-01-01 Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT) 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 Bioorg Med Chem Lett Article 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. Elsevier Science Ltd 2018-01-01 /pmc/articles/PMC5720837/ /pubmed/29169674 http://dx.doi.org/10.1016/j.bmcl.2017.11.028 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title_full Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title_fullStr Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title_full_unstemmed Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title_short Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT)
title_sort identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (an11736) as a potential development candidate for the treatment of animal african trypanosomiasis (aat)
topic Article
url 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
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