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

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.

C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies

“…Because of its high inhibitory capacity of PPP, mainly of PP2A, OA has been widely used to resemble AD manifestations in particular, but tauopathies in general, in both in vitro and in vivo models [54][55][56]67]. For instance, it has been described that SH-SY5Y neuroblastoma cultures show a loss of cell viability when challenged with OA at nanomolar concentrations during several hours of incubation [69]. A 20 h-exposition of SH-SY5Y cells to OA 20 nM indeed provoked a loss of about 30% in cell viability, measured by the MTT colorimetric dye, of about 30%.…”