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.

Figure 1

Selected N-propargylamines and metal chelators of therapeutic interest, together with the design of the molecules described herein (in color, the potential bioactive moiety).

Figure 2

Effect of compounds on SH-SY5Y cell viability. Basal bar corresponds to SH-SY5Y neuroblastoma cells only treated with culture medium. In each independent experiment, a batch of cells was treated with the toxic cocktail rotenone and oligomycin A (30 and 10 μM, respectively, R/O) as an example of the expected loss of cell viability elicited by a toxic stimulus. Data are means ± SEM of triplicates of at least five different cell cultures: ***p < 0.001 and **p < 0.01 with respect to basal.