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Letters in Organic Chemistry


ISSN (Print): 1570-1786
ISSN (Online): 1875-6255

Research Article

Synthesis and Biological Evaluation of Heteroarylnonanenitriles as Potential Antitrypanosomal Agents: Serendipitous Discovery of Novel Anticholinesterase Hits

Author(s): Albert Artigas, Irene Sola, Martin C. Taylor, M. Victoria Clos, Belen Perez, John M. Kelly and Diego Munoz-Torrero*

Volume 15, Issue 5, 2018

Page: [455 - 461] Pages: 7

DOI: 10.2174/1570178615666171219164459

Price: $65


We have recently developed three antitrypanosomal leads that feature a unit of huprine or (6-chloro-)tacrine linked to a 8-cyanooctyl side chain, which, unfortunately, exhibit very potent (low nanomolar) acetylcholinesterase (AChE) inhibitory activity, which might lead to unwanted cholinergic side-effects. Because huprine and tacrine moieties impart high acetylcholinesterasic potency, we have explored their replacement by alternative heteroaromatic systems (thiazolylbenzamido, quinoxalinecarboxamido, benzimidazolecarboxamido, and benzothiazolylamino moieties), while retaining the 8- cyanooctyl side chain. These structural modifications led to the desired drop in AChE inhibitory activity (low micromolar), albeit at the expense of the antitrypanosomal potency. However, despite the lower AChE inhibitory activity of the novel compounds compared to that of the initial leads, their potency is comparable to that of some AChE inhibitors currently approved for Alzheimer's disease (AD) treatment. They are brain permeable and less lipophilic than the leads, thereby emerging as interesting novel hits for future AChE inhibitor-based AD drug discovery programs.

Keywords: Alkanenitriles, antitrypanosomal agents, acetylcholinesterase inhibitors, brain permeability, phenotypic assays, in vitro assays.

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