New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
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Kota, Krishna P.
Cazares, Lisa H.
Terzić Jovanović, Nataša
Anđelković, Boban D.
Duplantier, Allen J.
Article (Published version)
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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
- Amer Chemical Soc, Washington
- 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]
- The peer-reviewed version: http://cer.ihtm.bg.ac.rs/handle/123456789/2935