The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease
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Nuss, Jon E.
Gomba, Laura M.
Burnett, James C.
Article (Published version)
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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 / Inhibition
Source:European Journal of Medicinal Chemistry, 2012, 53, 374-379
- Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
- 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]
- Peer-reviewed version of the article: http://cer.ihtm.bg.ac.rs/handle/123456789/971