Synthesis, Molecular Docking, and Preliminary Evaluation of 2‐(1,2,3‐Triazoyl)benzaldehydes As Multifunctional Agents for the Treatment of Alzheimer's Disease

• Published in: ChemMedChem 2020-04, Vol.15 (7), p.610-622
• Main Authors: Costa, Gabriel P., Baldinotti, Rodolfo S. M., Fronza, Mariana G., Nascimento, José Edmilson R., Dias, Ítalo F. C., Sonego, Mariana Souza, Seixas, Fabiana Kömmling, Collares, Tiago, Perin, Gelson, Jacob, Raquel G., Savegnago, Lucielli, Alves, Diego
• Format: Article
• Language: English
• Subjects: 1,2,3-triazoles; Acetylcholinesterase; Acetylcholinesterase - metabolism; Affinity; Alkynes; Alzheimer Disease - chemically induced; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid; Animals; Antioxidants; Behavior, Animal - drug effects; Benzaldehyde; Benzaldehydes - chemical synthesis; Benzaldehydes - chemistry; Benzaldehydes - pharmacology; Catalysts; Chemical synthesis; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cognitive ability; Copper; Cycloaddition; Disease Models, Animal; Glycogen; Glycogen synthase kinase 3; Glycogens; Iodides; Kinases; Ligands; Male; Medical treatment; Mice; Molecular docking; Molecular Docking Simulation; multitarget; Neurodegenerative diseases; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Secretase; Streptozocin; Therapeutic applications; Thiourea; Thioureas; Triethylamine; β-Site APP-cleaving enzymes
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900622

We described here our results on the use of thiourea as a ligand in the copper catalysed azide‐alkyne cycloaddition (CuAAC) of 2‐azidobenzaldehyde with alkynes. Reactions were performed reacting 2‐azidobenzaldehyde 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 °C under nitrogen atmosphere. The corresponding 2‐(1H‐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: β‐secretase (BACE), glycogen synthase kinase (GSK‐3β) and acetylcholinesterase (AChE). The three compounds with highest affinity, 5 a (2‐(4‐phenyl‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde), 5 b (2‐(4‐(p‐tolyl)‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde), and 5 d (2‐(4‐(4‐(tert‐butyl)phenyl)‐1H‐1,2,3‐triazol‐1‐yl)benzaldehyde) 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‐3β and AChE, compound 5 b was evaluated in a mouse model of AD induced by intracerebroventricular injection of streptozotocin (STZ). Our results indicate that 5 b (1 mg/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‐3β expression. Multifunctional agents: A range of 2‐(1H‐1,2,3‐triazoyl)benzaldehydes was synthesized by CuAAC reactions using thiourea as a ligand. Compounds were screened by molecular docking for their binding affinity for therapeutic targets in AD such as BACE, GSK‐3β and AChE as well as for their antioxidant potential to select the most promising drug for further studies.