American Chemical Society
jm7b01710_si_002.pdf (13.23 MB)

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

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journal contribution
posted on 2018-01-31, 00:00 authored by Jelena Konstantinović, Erkan Kiris, Krishna P. Kota, Johanny Kugelman-Tonos, Milica Videnović, Lisa H. Cazares, Nataša Terzić Jovanović, Tatjana Ž. Verbić, Boban Andjelković, Allen J. Duplantier, Sina Bavari, Bogdan A. Šolaja
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.