New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
AuthorsKonstantinović, Jelena M.
Kota, Krishna P.
Cazares, Lisa H.
Terzić Jovanović, Nataša
Anđelković, Boban D.
Duplantier, Allen J.
Article (Accepted 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]