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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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2012
Authors
Opsenica, Igor
Filipović, Vuk
Nuss, Jon E.
Gomba, Laura M.
Opsenica, Dejan
Burnett, James C.
Gussio, Rick
Šolaja, Bogdan
Bavari, Sina
Article (Published version)
,
Elsevier
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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).
Keywords:
Bioterrorism / Botulinum neurotoxin / Inhibition
Source:
European Journal of Medicinal Chemistry, 2012, 53, 374-379
Publisher:
  • 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:
  • Peer-reviewed version of the article: http://cer.ihtm.bg.ac.rs/handle/123456789/971

DOI: 10.1016/j.ejmech.2012.03.043

ISSN: 0223-5234

PubMed: 22516424

WoS: 000305863100040

Scopus: 2-s2.0-84861589629
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URI
http://cer.ihtm.bg.ac.rs/handle/123456789/2676
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