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

[Display omitted] 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 stud...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2018-01, Vol.28 (1), p.6-10
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antiprotozoal Agents - chemical synthesis
Antiprotozoal Agents - pharmacology
Antiprotozoal Agents - therapeutic use
Benzoxaborole
Boron Compounds - chemical synthesis
Boron Compounds - pharmacology
Boron Compounds - therapeutic use
Cattle
Lead optimisation
Mice
Protozoan
SAR
Structure-Activity Relationship
Trypanosoma congolense - drug effects
Trypanosoma vivax - drug effects
Trypanosomiasis
Trypanosomiasis, African - drug therapy
Trypanosomiasis, African - pathology
Trypanosomiasis, African - veterinary
Valine - analogs & derivatives
Valine - chemical synthesis
Valine - pharmacology
Valine - therapeutic use
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:[Display omitted] 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 IC50 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.11.028