RESUMEN
Botulinum neurotoxins (BoNTs) are the most toxic substances known to mankind and are the causative agents of the neuroparalytic disease botulism. Their ease of production and extreme toxicity have caused these neurotoxins to be classified as Tier 1 bioterrorist threat agents and have led to a sustained effort to develop countermeasures to treat intoxication in case of a bioterrorist attack. While timely administration of an approved antitoxin is effective in reducing the severity of botulism, reversing intoxication requires different strategies. In the present study, we evaluated ABS 252 and other mercaptoacetamide small molecule active-site inhibitors of BoNT/A light chain using an integrated multi-assay approach. ABS 252 showed inhibitory activity in enzymatic, cell-based and muscle activity assays, and importantly, produced a marked delay in time-to-death in mice. The results suggest that a multi-assay approach is an effective strategy for discovery of potential BoNT therapeutic candidates.
Asunto(s)
Toxinas Botulínicas Tipo A/antagonistas & inhibidores , Metaloproteasas/antagonistas & inhibidores , Neurotoxinas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Animales , Toxinas Botulínicas Tipo A/química , Células Cultivadas , Cristalografía por Rayos X , Descubrimiento de Drogas/métodos , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculos/efectos de los fármacos , Músculos/fisiología , Neurotoxinas/química , Inhibidores de Proteasas/química , Ratas Sprague-DawleyRESUMEN
This manuscript describes the preparation of an advanced intermediate toward the total synthesis of citrinadin A, featuring a [3+2] cycloaddition employing in situ generation of the dipole.
Asunto(s)
Alcaloides Indólicos/síntesis química , Reacción de Cicloadición , Alcaloides Indólicos/química , Estructura Molecular , EstereoisomerismoRESUMEN
This manuscript describes the enantioselective preparation of a spirooxindole that is suited for advancedment to either Citrinadin A or B.
RESUMEN
This manuscript describes an enantioselective synthesis of the naturally occurring alkaloid citrinadin B. The synthetic effort revealed an anomaly in the original structural assignment that has led to the proposal of a stereochemical revision. This revision is consistent with the structures previously reported for a closely related family of alkaloids, PF1270A-C. The synthesis is convergent and employs a stereoselective intermolecular nitrone cyloaddition reaction as a key step.
Asunto(s)
Alcaloides Indólicos/química , Alcaloides Indólicos/síntesis química , Compuestos Orgánicos , Estereoisomerismo , Especificidad por SustratoRESUMEN
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.