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New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model

Authorized Users Only
2018
Authors
Konstantinović, Jelena M.
Kiris, Erkan
Kota, Krishna P.
Kugelman-Tonos, Johanny
Videnović, Milica
Cazares, Lisa H.
Terzić-Jovanović, Nataša
Verbić, Tatjana
Anđelković, Boban D.
Duplantier, Allen J.
Bavari, Sina
Šolaja, Bogdan
Article (Published version)
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Abstract
The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.
Source:
Journal of Medicinal Chemistry, 2018, 61, 4, 1595-1608
Publisher:
  • Amer Chemical Soc, Washington
Projects:
  • The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
  • U.S. Defense Threat Reduction Agency/Joint Science and Technology Office
  • Serbian Academy of Sciences and Arts
  • National Institute of Allergy and Infectious Diseases (U.S.) [5-U01AI082051-02, R33-AI101387]
Note:
  • The peer-reviewed version: http://cer.ihtm.bg.ac.rs/handle/123456789/2935

DOI: 10.1021/acs.jmedchem.7b01710

ISSN: 0022-2623

PubMed: 29385334

WoS: 000426220900014

Scopus: 2-s2.0-85042675131
[ Google Scholar ]
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URI
http://cer.ihtm.bg.ac.rs/handle/123456789/2325
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