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
; 53: 374-9, 2012 Jul.
Article
em En
| MEDLINE
| ID: mdl-22516424
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).
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
/
Tiofenos
/
Toxinas Botulínicas Tipo A
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article