New tetracyclic tacrine analogs containing pyrano[2,3-c]pyrazole: Efficient synthesis, biological assessment and docking simulation study

• Published in: European journal of medicinal chemistry 2015-01, Vol.89, p.296-303
• Main Authors: Khoobi, Mehdi, Ghanoni, Farzaneh, Nadri, Hamid, Moradi, Alireza, Pirali Hamedani, Morteza, Homayouni Moghadam, Farshad, Emami, Saeed, Vosooghi, Mohsen, Zadmard, Reza, Foroumadi, Alireza, Shafiee, Abbas
• Format: Article
• Language: English
• Subjects: Acetylcholinesterase; Alzheimer's disease; Animals; Butyrylcholinesterase - blood; Cell Death - drug effects; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Docking study; Drug Design; Electrophorus; Heterocyclic Compounds, 4 or More Rings - chemical synthesis; Heterocyclic Compounds, 4 or More Rings - chemistry; Heterocyclic Compounds, 4 or More Rings - pharmacology; Horses; Hydrogen Peroxide - pharmacology; Kinetics; Molecular Docking Simulation; Neuroprotective activity; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; PC12 Cells; Pyrans - chemistry; Pyrazoles - chemistry; Rats; Tacrine; Tacrine - analogs & derivatives; Tacrine - chemical synthesis; Tacrine - chemistry; Tacrine - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.10.049

A new series of tacrine-based acetylcholinesterase (AChE) inhibitors 7a–l were designed by replacing the benzene ring of tacrine with aryl-dihydropyrano[2,3-c]pyrazole. The poly-functionalized hybrid molecules 7a–l were efficiently synthesized through multi-component reaction and subsequent Friedländer reaction between the obtained pyrano[2,3-c]pyrazoles and cyclohexanone. Most of target compounds showed potent and selective anti-AChE activity at sub-micromolar range. The most potent compound 7h bearing a 3,4-dimethoxyphenyl group was more active than reference drug tacrine. The representative compound 7h could significantly protect neurons against oxidative stress as potent as quercetin at low concentrations. The docking study of compound 7h with AChE enzyme revealed that the (R)-enantiomer binds preferably to CAS while the (S)-enantiomer prone to be a PAS binder. A new series of tacrine-based compounds 7a–l were designed and synthesized as AChE inhibitors. The most potent compound 7h bearing a 3,4-dimethoxyphenyl group was more active than reference drug tacrine. [Display omitted] •A series of tacrine-based compounds 7a–l were synthesized as AChE inhibitors.•Compound 7h bearing a 3,4-dimethoxyphenyl group was the most active derivative.•Compound 7h with IC50 = 0.19 μM was more potent than reference drug tacrine.•Compound 7h could significantly protect neurons against oxidative stress.•Docking study showed that (R)-7h preferably binds to CAS while (S)-7h binds to PAS.