Botulinum neurotoxin serotype A inhibitors: Small-molecule mercaptoacetamide analogs

Botulinum neurotoxin elicits its paralytic activity through a zinc-dependant metalloprotease that cleaves proteins involved in neurotransmitter release. Currently, no drugs are available to reverse the effects of botulinum intoxication. Herein we report the design of a novel series of mercaptoacetamide small-molecule inhibitors active against botulinum neurotoxin serotype A. These analogs show low micromolar inhibitory activity against the isolated enzyme. Structure–activity relationship studies for a series of mercaptoacetamide analogs of 5-amino-3-phenylpyrazole reveal components essential for potent inhibitory activity.

Botulinum neurotoxin serotype A, interferes with neurotransmitter release via a metalloprotease-mediated process. We designed a novel series of inhibitors active against the enzyme. SAR studies revealed components essential for low micromolar activity.Figure optionsDownload as PowerPoint slide