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

2012
Authors
Opsenica, Igor
Filipović, Vuk

Nuss, Jon E.
Gomba, Laura M.
Opsenica, Dejan

Burnett, James C.
Gussio, Rick
Šolaja, Bogdan

Bavari, Sina
Article (Accepted Version)

Metadata
Show full item recordAbstract
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).
Keywords:
Bioterrorism / Botulinum neurotoxin / InhibitionSource:
European Journal of Medicinal Chemistry, 2012, 53, 374-379Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
Projects:
- National Institute of Allergy and Infectious Diseases (USA) [5-U01 AI082051-02]
- NATOs Public Diplomacy Division
- National Cancer Institute
- National Institutes of Health (USA) [HHSN261200800001E]
Note:
- This is the peer-reviewed version of the article: Opsenica, I., Filipovic, V., Nuss, J.E., Gomba, L.M., Opsenica, D., Burnett, J.C., Gussio, R., Solaja, B.A., Bavari, S., European Journal of Medicinal Chemistry, 2012, 53, 374–379. https://doi.org/10.1016/j.ejmech.2012.03.043
- http://cer.ihtm.bg.ac.rs/handle/123456789/2676
DOI: 10.1016/j.ejmech.2012.03.043
ISSN: 0223-5234
PubMed: 22516424