Synthesis, docking and ADME prediction of novel 1,2,3-triazole-tethered coumarin derivatives as potential neuroprotective agents

In an attempt to find potential neuroprotective agents, a series of novel 3-(1-((1-(substituted phenyl)-1 H -1,2,3-triazol-4-yl) methoxyimino) ethyl)-2 H -chromen-2-one derivatives 6a – j were synthesized by using “click reaction” and evaluated for their in vitro neuroprotectivity and toxicity against H 2 O 2 -induced PC12 cell lines by using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction assay. Most of them exhibited moderate to good activity in which compound 6e was found to have significant protectivity with cell viability of 94.51 ± 0.68% at 50 µg/ml concentration and half-maximal effective concentration (EC 50 ) value of 14.04 µg/ml against injured PC12 cell lines and low toxicity with half-maximal cytotoxic concentration (CC 50 ) value of 544.88 µg/ml. Furthermore, molecular docking was carried out in order to understand plausible binding modes of novel derivatives with the active site of glycogen synthase kinase-3β enzyme, and the results were well complemented by the in vitro neuroprotective results against H 2 O 2 -induced PC12 cell lines. Additionally, in silico ADME properties showed drug likeness with good oral absorption and moderate blood–brain barrier permeability. The structures of all the synthesized compounds were confirmed by 1 H NMR, 13 C NMR, IR and LC–MS analyses.