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 5c and 5d exhibited the most desirable multiple functions for AD; they were strong hAChE inhibitors with IC₅₀ 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 IC₅₀ = 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 5d, which was 8 times more effective than curcumin with IC₅₀ = 0.74 μM and 76% inhibition at 10 μM. Compounds 5c and 5d showed strong BACE-1 inhibition at the submicromolar level with IC₅₀ = 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 IC₅₀ = 5.15 and 2.42 μM, respectively. They also had antioxidant activities and showed satisfactory metal-chelating properties toward Fe⁺², Zn⁺², and Cu⁺², inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety upon normal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by online prediction. Taken together, these multifunctional properties highlight that compounds 5c and 5d can serve as promising candidates for the further development of multifunctional drugs against AD.