New tacrine-acridine hybrids as promising multifunctional drugs for potential treatment of Alzheimer's disease.

The synthesis, biological tests, and computer modeling of a series of novel promising tacrine hybrids for the therapy of Alzheimer's disease are reported. Firstly, new tacrine-acridine hybrids with different carbon linker lengths were synthesized. Secondly, all the compounds were tested in vitro for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzyme activity. After that, the most promising compound 3d was tested using the amyloid-β aggregation assay. To evaluate possible toxic effects, cytotoxicity tests were conducted. The most active compound 3d (IC  = 7.6 pM for AChE and 1.7 pM for BuChE) appeared to be a much more active inhibitor than tacrine (IC  = 89.9 nM for AChE and 14.9 nM for BuChE). At the highest concentration (100 μM), 3d exhibited 57.77% activity, retaining it as the concentration decreased: 50 μM - 54.74%, 20 μM - 48.28%, 10 μM - 31.66%. The compound showed no significant cytotoxic effect at the tested concentrations. At the end, docking studies using methods of computer modeling were performed to visualize the binding mode of the inhibitor 3d. It showed dual-binding mode for AChE, by binding to the catalytic anionic site and the peripheral anionic site simultaneously. Thus, compound 3d is a promising multitarget hybrid that can be used for the treatment of Alzheimer's disease.