Synthesis and functional survey of new Tacrine analogs modified with nitroxides or their precursors

•Synthesis of new nitroxide-based Tacrine derivatives and analogs.•Characterization of new compounds with spectral techniques including NMR, MS.•Testing of new compounds confirmed their dual (antioxidant and AChEI) activity.•Molecular modeling and docking supported the biological findings.

A series of new Tacrine analogs modified with nitroxides or pre-nitroxides on 9-amino group via methylene or piperazine spacers were synthesized; the nitroxide or its precursors were incorporated into the Tacrine scaffold. The new compounds were tested for their hydroxyl radical and peroxyl radical scavenging ability, acetylcholinesterase inhibitor activity and protection against Aβ-induced cytotoxicity. Based on these assays, we conclude that Tacrine analogs connected to five and six-membered nitroxides via piperazine spacers (9b, 9b/HCl and 12) exhibited the best activity, providing direction for further development of additional candidates with dual functionality (anti Alzheimer's and antioxidant).

Graphical abstractNew Tacrine derivatives have been synthesized by modifying the amino group or incorporating nitroxide rings or sterically hindered amines into the Tacrine molecule. Compounds with piperazine spacers exhibited the best ROS scavenging and anti Alzheimer's activity.Figure optionsDownload full-size imageDownload as PowerPoint slide