Modified Tacrine Derivatives as Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Synthesis, Biological Evaluation, and Molecular Modeling Study.

To develop multitarget-directed ligands (MTDLs) as potential treatments for Alzheimer's disease (AD) and to shed light on the effect of the chromene group in designing these ligands, 35 new tacrine-chromene derivatives were designed, synthesized, and biologically evaluated. Compounds and exhibited the most desirable multiple functions for AD; they were strong AChE inhibitors with IC values of 0.44 and 0.25 μM, respectively. Besides, their potent BuChE inhibitory activity was 10- and 5-fold more active than rivastigmine with IC = 0.08 and 0.14 μM, respectively. Moreover, they could bind to the peripheral anionic site (PAS), influencing Aβ aggregation and decreasing Aβ-related neurodegeneration, especially compound , which was 8 times more effective than curcumin with IC = 0.74 μM and 76% inhibition at 10 μM. Compounds and showed strong BACE-1 inhibition at the submicromolar level with IC = 0.38 and 0.44 μM, respectively, which almost doubled the activity of curcumin. They also showed single-digit micromolar inhibitory activity against MAO-B with IC = 5.15 and 2.42 μM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe, Zn, and Cu, inhibiting oxidative stress in AD brains. Furthermore, compounds and showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that and were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds and can serve as promising candidates for the further development of multifunctional drugs against AD.