Synthesis and biological evaluation of inhibitors of botulinum neurotoxin metalloprotease

ORGN 162

Julia R. Widom, julia-widom@northwestern.edu, Department of Chemistry, University of Pittsburgh, 5549 Darlington Road, Pittsburgh, PA 15217
Based on the HTS hit NSC 357756, we have developed a new series of inhibitors of BoNTs. Botulinum neurotoxins (BoNTs), produced by bacteria Clostridium botulinum in contaminated food, are the deadliest toxins known. Among the seven BoNT serotypes (A-G), BoNT A has been used for the treatment of muscle hyperactivity and spasticity disorders, as well as cosmetic applications, raising the concern of overdosing. Furthermore, BoNTs have been recognized as a potential biological weapon. Based on the reported inhibitory activities of NSC 240898 and NSC 377363, we synthesized two series of benzimidazole and indole analogs. A key aspect of our synthesis was the use of microwave heating for SNAr reactions, Sonogashira couplings, and Au(I)-catalyzed indole formations.