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

Bioorg Med Chem Lett. 2018 Jan 1;28(1):6-10. doi: 10.1016/j.bmcl.2017.11.028. Epub 2017 Nov 20.

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.

Keywords: Benzoxaborole; Cattle; Lead optimisation; Protozoan; SAR; Trypanosomiasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / pharmacology
  • Antiprotozoal Agents / therapeutic use
  • Boron Compounds / chemical synthesis*
  • Boron Compounds / pharmacology
  • Boron Compounds / therapeutic use
  • Cattle
  • Mice
  • Structure-Activity Relationship
  • Trypanosoma congolense / drug effects
  • Trypanosoma vivax / drug effects
  • Trypanosomiasis, African / drug therapy*
  • Trypanosomiasis, African / pathology
  • Trypanosomiasis, African / veterinary
  • Valine / analogs & derivatives*
  • Valine / chemical synthesis
  • Valine / pharmacology
  • Valine / therapeutic use

Substances

  • AN11736
  • Antiprotozoal Agents
  • Boron Compounds
  • Valine