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The formation of amyloid- β (A β) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting A β deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of A β deposits in the brain. The probe had excellent fluorescent properties with an emission maximum above 720 nm upon binding to A β aggregates with affinity of 445.0 nM (K d). Furthermore, ZT-1 exhibited good biostability, photostability, and binding selectivity toward A β 1-42 aggregates by in vitro fluorescence staining experiments. In vivo NIRF imaging result also revealed that our probe could efficiently differentiate transgenic and wild-type mice. All these studies indicated that ZT-1 is a promising fluorescent probe for A β plaques in the AD brains. Image 1 • A probe ZT-1 for the detection of A β deposits in the brain was synthesized and evaluated. • ZT-1 exhibited good biostability, photostability, and binding selectivity toward A β 1-42 aggregates. • ZT-1 could efficiently differentiate transgenic and wild-type mice by in vivo NIRF imaging. [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]

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]

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]

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]

Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation. The inhibitory activity of the derivatives against the self-fibrillation of the hexapeptide AcPHF6 was initially screened by ThT fluorescence assay. Using circular dichroism and transmission electron microscopy, compound 30 showed the most potent inhibitory activity against AcPHF6 self-fibrillation. Compound 30 was further confirmed to inhibit the aggregation of full-length 2N4R tau protein by a heparin-induced mechanism. In addition, we investigated the anti-inflammatory activity of compound 30, and showed that compared with sodium usnate, it reduced NO release in LPS-stimulated mouse microglia BV2 cells. More importantly, 30 showed significant protective effects against okadaic acid-induced memory impairment in rats. Thus, 30 was a novel tau-aggregation and neuroinflammation inhibitor that represented a potential therapeutic candidate for AD. Image 1 • Two series of usnic acid derivatives were synthesized and evaluated as dual inhibitors of tau-aggregation and neuroinflammation. • Compound 30 exhibited remarkable inhibitory activities against AcPHF6 and full-length tau aggregation. • Compound 30 showed a low cytotoxicity and reduced NO release in LPS-stimulated BV2 cells. • Compounds 30 reversed okadaic acid-induced memory impairment in rats. [ABSTRACT FROM AUTHOR]