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Abstract The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC 50, 0.075 μM for ee AChE and 0.75 μM for h AChE) and Monoamine oxidase B (MAO-B) inhibition (IC 50 , 7.4 μM for h MAO-B), excellent antioxidant activity (71.7 μM of IC 50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, h AChE-induced A β aggregation. Moreover, 7d possessed neuroprotective potency against H 2 O 2 -induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD. Graphical abstract Image 1 Highlights • A series of donepezil-BHT derivatives through two modifications were rational designed, synthesized and evaluated. • Most of the compounds showed good inhibitory activities against AChE and MAO-B as well as remarkable antioxidant activities. • 7d displayed a balanced multifunctional profile covering an intriguing AChE and MAO-B inhibition, antioxidant activity. • 7d possessed neuroprotection against H 2 O 2 -induced oxidative damage and LPS-stimulated inflammation on cell level. • 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity and hepatotoxicity. [ABSTRACT FROM AUTHOR]

A series of multitargeted 8-hydroxyquinoline derivatives were designed and synthesized for the treatment of Alzheimer’s disease (AD). In vitro studies indicated that most of the prepared compounds exhibited significant inhibitory effects against self-induced A β 1−42 aggregation and potential antioxidant properties especially compound 5b (IC 50  = 5.64 μM for self-induced A β aggregation; the oxygen radical absorbance capacity using fluorescein (ORAC-FL) value is 2.63 Trolox equivalents). Notably, 5b can chelate biometals and inhibit Cu 2+ /Zn 2+ -induced A β 1−42 aggregation. The cell assays showed that 5b had excellent protective effects against oxidative toxin H 2 O 2 and presented low neurotoxicity in PC12 cells. Furthermore, 5b could penetrate the blood–brain barrier (BBB) in vitro and did not show any acute toxicity in mice at doses up to 2000 mg/kg in vivo . Our findings provide a rationale for the potential application of compound 5b as a lead compound in AD therapy. [ABSTRACT FROM AUTHOR]

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer’s disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid- β (A β ) aggregation and human monoamine oxidase B ( h MAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5 , exhibited excellent potency for inhibition of self-induced A β 1–42 aggregation (91.3 ± 2.1%, 25 μM), inhibition of h MAO-B (IC 50 , 1.73 ± 0.39 μM), antioxidant effects (43.4 ± 2.6 μM of IC 50 by DPPH method, 0.67 ± 0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H 2 O 2 -induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs. [ABSTRACT FROM AUTHOR]

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced β -amyloid (A β ) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation. [ABSTRACT FROM AUTHOR]

A series of coumarin-pargyline hybrids ( 4a-x ) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid- β (A β ) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC 50 , 0.027 ± 0.004 μ M for MAO-B; 3.275 ± 0.040 μ M for MAO-A) and A β 1-42 aggregation (54.0 ± 1.1%, 25 μ M). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy. [ABSTRACT FROM AUTHOR]

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC 50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, A β interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties ( in silico ). Among them, 5c demonstrated excellent AChE inhibition (IC 50 : 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu 2+ -induced A β 1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 μ M). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against A β 1-42 -induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy. [ABSTRACT FROM AUTHOR]

Abstract A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (h MAO-B). In particular, 3 and 7 showed the better inhibitory activity for h MAO-B (IC 50 = 3.91 ± 0.23 μ M, 0.90 ± 0.01 μ M) respectively. Compound 3 (IC 50 = 46.95 ± 0.21 μ M for DPPH, 1.43 and 1.74 trolox equivalent by ABTS and FRAP method respectively), and 7 (IC 50 = 35.33 ± 0.15 μ M for DPPH, 1.70 and 1.97 trolox equivalent by ABTS method and FRAP method respectively) have excellent antioxidant effects. Cellular assay shown that 3 and 7 had lower toxicity and were resistant to neurotoxicity induced by oxidative toxins (H 2 O 2 , rotenone and oligomycin-A). More importantly, the selected compounds have neuroprotective effects against ROS generation, H 2 O 2 -induced apoptosis and a significant in vitro anti-inflammatory activity. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that 3 and 7 would be predominant to cross the blood-brain barrier. In this study, mouse microglia BV2 cells were used to establish cell oxidative stress injury model with H 2 O 2 and to explore the protective effect and mechanism of 3 and 7. In general, 3 and 7 can be considered candidates for potential treatment of AD. Graphical abstract Image 1 Highlights • A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. • Most of the compounds showed moderate to good inhibitory activities against MAO-B as well as remarkable antioxidant activities. • Compounds 3 and 7 displayed a balanced multifunctional profile having MAO-B inhibition, excellent antioxidant activity. • Compounds 3 and 7 possessed significant neuroprotection against H2O2-induced oxidative damage on PC12 cells and BV2 microglial cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 microglial cells. • Compounds 3 and 7 have lower toxicity and could cross the blood-brain barrier. [ABSTRACT FROM AUTHOR]

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer’s disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC 50 value of 5.12 μM for h MAO-A and 0.816 μM for h MAO-B), moderate inhibition of A β aggregation (75.1% at 20 μM), metal chelation, control of ROS generation and antioxidant activity (ORAC = 3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment. [ABSTRACT FROM AUTHOR]