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

To develop multitarget-directedligands (MTDLs) as potentialtreatmentsfor Alzheimer's disease (AD) and to shed light on the effectof the chromene group in designing these ligands, 35 new tacrine-chromenederivatives were designed, synthesized, and biologically evaluated.Compounds 5c and 5d exhibited the most desirablemultiple functions for AD; they were strong hAChEinhibitors with IC50 values of 0.44 and 0.25 & mu;M,respectively. Besides, their potent BuChE inhibitory activity was10- and 5-fold more active than rivastigmine with IC50 =0.08 and 0.14 & mu;M, respectively. Moreover, they could bind tothe peripheral anionic site (PAS), influencing A & beta; aggregationand decreasing A & beta;-related neurodegeneration, especially compound 5d, which was 8 times more effective than curcumin with IC50 = 0.74 & mu;M and 76% inhibition at 10 & mu;M. Compounds 5c and 5d showed strong BACE-1 inhibition atthe submicromolar level with IC50 = 0.38 and 0.44 & mu;M,respectively, which almost doubled the activity of curcumin. Theyalso showed single-digit micromolar inhibitory activity against MAO-Bwith IC50 = 5.15 and 2.42 & mu;M, respectively. Theyalso had antioxidant activities and showed satisfactory metal-chelatingproperties toward Fe+2, Zn+2, and Cu+2, inhibiting oxidative stress in AD brains. Furthermore, compounds 5c and 5d showed acceptable relative safety uponnormal cells SH-SY5Y and HepG2. It was shown that 5c and 5d were blood-brain barrier (BBB) penetrants by onlineprediction. Taken together, these multifunctional properties highlightthat compounds 5c and 5d can serve as promisingcandidates for the further development of multifunctional drugs againstAD.