The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease
Authors
Opsenica, IgorFilipović, Vuk
Nuss, Jon E.
Gomba, Laura M.
Opsenica, Dejan M.
Burnett, James C.
Gussio, Rick
Šolaja, Bogdan A.
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). (C) 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
Bioterrorism / Botulinum neurotoxin / InhibitionSource:
European Journal of Medicinal Chemistry, 2012, 53, 374-379Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Paris
Funding / 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., 2012. The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease. European Journal of Medicinal Chemistry 53, 374–379. https://doi.org/10.1016/j.ejmech.2012.03.043
DOI: 10.1016/j.ejmech.2012.03.043
ISSN: 0223-5234
PubMed: 22516424
WoS: 000305863100040
Scopus: 2-s2.0-84861589629
Collections
Institution/Community
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Opsenica, Igor AU - Filipović, Vuk AU - Nuss, Jon E. AU - Gomba, Laura M. AU - Opsenica, Dejan M. AU - Burnett, James C. AU - Gussio, Rick AU - Šolaja, Bogdan A. AU - Bavari, Sina PY - 2012 UR - https://cherry.chem.bg.ac.rs/handle/123456789/2787 AB - 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). (C) 2012 Elsevier Masson SAS. All rights reserved. PB - Elsevier France-Editions Scientifiques Medicales Elsevier, Paris T2 - European Journal of Medicinal Chemistry T1 - The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease VL - 53 SP - 374 EP - 379 DO - 10.1016/j.ejmech.2012.03.043 ER -
@article{ author = "Opsenica, Igor and Filipović, Vuk and Nuss, Jon E. and Gomba, Laura M. and Opsenica, Dejan M. and Burnett, James C. and Gussio, Rick and Šolaja, Bogdan A. and Bavari, Sina", year = "2012", 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). (C) 2012 Elsevier Masson SAS. All rights reserved.", publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Paris", journal = "European Journal of Medicinal Chemistry", title = "The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease", volume = "53", pages = "374-379", doi = "10.1016/j.ejmech.2012.03.043" }
Opsenica, I., Filipović, V., Nuss, J. E., Gomba, L. M., Opsenica, D. M., Burnett, J. C., Gussio, R., Šolaja, B. A.,& Bavari, S.. (2012). The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease. in European Journal of Medicinal Chemistry Elsevier France-Editions Scientifiques Medicales Elsevier, Paris., 53, 374-379. https://doi.org/10.1016/j.ejmech.2012.03.043
Opsenica I, Filipović V, Nuss JE, Gomba LM, Opsenica DM, Burnett JC, Gussio R, Šolaja BA, Bavari S. The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease. in European Journal of Medicinal Chemistry. 2012;53:374-379. doi:10.1016/j.ejmech.2012.03.043 .
Opsenica, Igor, Filipović, Vuk, Nuss, Jon E., Gomba, Laura M., Opsenica, Dejan M., Burnett, James C., Gussio, Rick, Šolaja, Bogdan A., Bavari, Sina, "The synthesis of 2,5-bis(4-amidinophenyl)thiophene derivatives providing submicromolar-range inhibition of the botulinum neurotoxin serotype A metalloprotease" in European Journal of Medicinal Chemistry, 53 (2012):374-379, https://doi.org/10.1016/j.ejmech.2012.03.043 . .