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
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. ŠolajaThe 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.