Costa_2020_ChemMedChem__

We described here our results on the use of thiourea as a ligand in the copper catalysed azide-alkyne cycloaddition (CuAAC) of 2-azidobenzaldheyde with alkynes. Reactions were performed reacting 2-azidobenzaldheyde with a range of terminal alkynes using 10 mol% of copper iodide as a catalyst, 20 mol% of thiourea as a ligand, triethylamine as base, DMSO as solvent at 100 degrees C under nitrogen atmosphere. The corresponding 2-(1 H -1,2,3-triazoyl)-benzaldehydes (2-TBH) were obtained in moderated to excellent yields and according our experiments, the use of thiourea decreases the formation of side products. The obtained compounds were screened for their binding affinity with multiple therapeutic targets of AD by molecular docking: beta-secretase (BACE), glycogen synthase kinase (GSK-3beta) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5a , 5b and 5d were selected and evaluated on its antioxidant effect, in view of select the most promising one to perform the in vivo validation . Due the antioxidant potential ally to the affinity with BACE, GSK-3beta and AChE, compound 5b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5b (1mg/kg) treatment during 20 days is able to reverse the cognitive and memory impairment induced by STZ trough the modulation of AChE activity, amyloid cascade and GSK-3beta expression.