In Silico Prediction of the Toxic Potential of Neuroprotective Bifunctional Molecules Based on Chiral N-Propargyl-1,2-amino Alcohol Derivatives.

Eva Ramos,Raquel L Arribas,Eva M García-Frutos,Rocío Lajarín-Cuesta,Laura González-Lafuente,Alejandro Romero,Cristóbal De Los Ríos,Javier Egea

doi:10.1021/acs.chemrestox.0c00519

Abstract

N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities. We obtained several neuroprotective molecules, chiral 1,2-amino alcohols and 1,2-diamines, able to reduce by almost 70% the rotenone and oligomycin A-induced damage in SH-SY5Y cells. Furthermore, some molecules assessed also counteracted the toxicity evoked by the Ser/Thr phosphatase inhibitor okadaic acid. Before extrapolating these data to preclinical studies, we analyze the molecules through an in silico prediction system to detect carcinogenicity risk or other toxic effects. In light of these promising results, these molecules may be considered as a lead family of neuroprotective and relatively safe compounds.

Highlights

N-Propargylamines are useful synthetic scaffolds for the synthesis of bioactive molecules, and in addition, they possess important pharmacological activities
1,2-amino alcohols have been studied as potential drugs for neurodegenerative diseases due to their role in regulating brain metal concentrations, which are altered in Alzheimer’s disease (AD) patients and involved in the acceleration of the β-amyloidinduced neuronal damage.[21]
These observations prompted us to hypothesize that homopropargylic compounds, conveniently transformed to present a potentially bioactive N-propargylamide moiety linked to a chiral 1,2-amino alcohol, would afford interesting pharmacodynamic and pharmacokinetic properties

Summary

DNA binding alerts

The administration of OA to neuronal cultures is a well-described AD in vitro model, in which tauopathy is the source of neuronal damage In this scenario, cells reduced their viability after the incubation with OA to 38%; the loss of neuron viability was counteracted by the administration of compounds 3a, 3b, 3d, 3e, or 4e at 0.3 μM, analogously to the protection provided by the anti-AD drug memantine.[27]. Five N-propargylamides have shown potential neuroprotective properties against two toxic stimuli related to neurodegeneration at sub-micromolar concentrations These results prompt us to continue the study of chiral propargylamides as new chemical entities with promising biological activities for the treatment of neurodegenerative diseases. All coauthors read and approved the final version of the manuscript

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES