The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease

Eur J Med Chem. 2012 Jul:53:374-9. doi: 10.1016/j.ejmech.2012.03.043. Epub 2012 Mar 30.

Abstract

Botulinum neurotoxins (BoNTs), composed of a family of seven serotypes (categorized A-G), are the deadliest of known biological toxins. The activity of the metalloprotease, light chain (LC) component of the toxins is responsible for causing the life-threatening paralysis associated with the disease botulism. Herein we report significantly more potent analogs of novel, lead BoNT serotype A LC inhibitor 2,5-bis(4-amidinophenyl)thiophene (K(i) = 10.88 μM ± 0.90 μM). Specifically, synthetic modifications involved simultaneously replacing the lead inhibitor's terminal bis-amidines with secondary amines and the systematic tethering of 4-amino-7-chloroquinoline substituents to provide derivatives with K(i) values ranging from 0.302 μM (± 0.03 μM) to 0.889μM (± 0.11 μM).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Botulinum Toxins, Type A / antagonists & inhibitors*
  • Botulinum Toxins, Type A / chemistry
  • Chemistry Techniques, Synthetic
  • Dose-Response Relationship, Drug
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*

Substances

  • Protease Inhibitors
  • Thiophenes
  • Botulinum Toxins, Type A