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

•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.

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.

Graphical abstractA 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.Figure optionsDownload full-size imageDownload as PowerPoint slide