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

• Published in: Journal of medicinal chemistry Vol. 61; no. 4; pp. 1595 - 1608
• Main Authors: Konstantinović, Jelena, Kiris, Erkan, Kota, Krishna P, Kugelman-Tonos, Johanny, Videnović, Milica, Cazares, Lisa H, Terzić Jovanović, Nataša, Verbić, Tatjana Ž, Andjelković, Boban, Duplantier, Allen J, Bavari, Sina, Šolaja, Bogdan A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22-02-2018
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01710

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.