Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model
Sina Bavari, Johanny Kugelman-Tonos, Nataša Terzić Jovanović, Boban Andjelković, Bogdan A. Šolaja, Lisa H. Cazares, Milica Videnović, Allen J. Duplantier, Jelena Konstantinović, Krishna P. Kota, Tatjana Ž. Verbić, Erkan Kiris
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b01710

DOI: 10.1021/acs.jmedchem.7b01710

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