Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT). Issue 1 (1st January 2018)

• Record Type: Journal Article
• 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
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 1(2018)
• Page Start: 6
• Page End: 10
• Publication Date: 2018-01-01
• Subjects: Benzoxaborole -- Trypanosomiasis -- Cattle -- SAR -- Lead optimisation -- Protozoan; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.11.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.