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

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 = 10.881 mu M +/- 0.90 mu M). 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 mu M (+/- 0.03 mu M) to 0.889 mu M (+/- 0.11 mu M).