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Alzheimer's disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid–donepezil–rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of 4′-OH flurbiprofen Mannich base derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound 8n demonstrated the best inhibitory effects on self-induced A β 1-42 aggregation (65.03% at 25.0 μM). Moreover, this representative compound also exhibited good antioxidant activity, biometal chelating ability and anti-neuroinflammatory activity in vitro. Furthermore, compound 8n displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 8n as promising candidate for further development of multi-functional drugs against AD. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel salicylamide derivatives were synthesized. • Most compounds showed selective AChE inhibitory and significant antioxidant activities. • Some compounds exhibited good inhibition of self- or Cu2+-induced A β aggregation. • Some compounds exhibited moderate effect on the disaggregation of A β aggregation. • Compound 15b showed good anti-neuroinflammation activity and BBB permeability. Abstract A series of salicylamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives were selective AChE inhibitors. They showed good inhibitory activities of self- and Cu2+-induced A β 1–42 aggregation, and significant antioxidant activities. Among them, compound 15b exhibited good inhibitory activity toward Rat AChE and Ee AChE with IC 50 value of 10.4 μM and 15.2 μM, respectively. Moreover, 15b displayed high antioxidant activity (2.46 Trolox equivalents), good self- and Cu2+-induced A β 1–42 aggregation inhibitory potency (42.5% and 31.4% at 25.0 μM, respectively) and moderate disaggregation ability to self- and Cu2+-induced A β 1–42 aggregation fibrils (23.4% and 27.0% at 25 μM, respectively). Furthermore, 15b also showed biometal chelating abilities, anti-neuroinflammatory ability and BBB permeability. These multifunctional properties indicated compound 15b was worthy of being chosen for further pharmacokinetics, toxicity and behavioral researches to test its potential for AD treatment. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of 2,5-dihydroxyterephthalamide derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. In vitro assays demonstrated that most of the derivatives exhibited good multifunctional activities. Among them, compound 9d showed the best inhibitory activity against both Rat AChE and Ee AChE (IC 50 = 0.56 μM and 5.12 μM, respectively). Moreover, 9d exhibited excellent inhibitory effects on self-induced A β 1–42 aggregation (IC 50 = 3.05 μM) and Cu2+-induced A β 1–42 aggregation (71.7% at 25.0 μM), and displayed significant disaggregation ability to self- and Cu2+-induced A β 1–42 aggregation fibrils (75.2% and 77.2% at 25.0 μM, respectively). Furthermore, 9d also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activities and appropriate BBB permeability. These multifunctional properties highlight 9d as promising candidate for further studies directed to the development of novel drugs against AD. [ABSTRACT FROM AUTHOR]

A series of pterostilbene β -amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for Ee AChE (IC 50  = 24.04 μM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H 2 O 2 -induced PC-12 cell injury. Moreover, 5f also showed self-induced A β 1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro . These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD. [ABSTRACT FROM AUTHOR]

A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC 50 values of 2.11 μM and 1.56 μM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC 50 value of 2.68 μM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Considering the complex etiology of Alzheimer’s disease (AD), multifunctional agents may be beneficial for the treatment of this disease. A series of DL -3- n -butylphthalide-Edaravone hybrids were designed, synthesized and evaluated as novel dual inhibitors of amyloid- β aggregation and monoamine oxidases. Among them, compounds 9a – d exhibited good inhibition of self-induced A β 1-42 aggregation with inhibition ratio 57.7–71.5%. For MAO, these new hybrids exhibited good balance of inhibition for MAO-A and MAO-B. In addition, all target compounds retained the antioxidant activity of edaravone, showed equal or better antioxidant activity than edaravone. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compounds 9a – d would be able to cross the blood-brain barrier and reach their biological targets in the central nervous system. The promising results in all assays demonstrated that the strategy behind the designing of compounds was rational and favourable. Taken together, these preliminary findings suggested that the compounds with the strongest bioactivity deserves further investigated for pharmacological development in AD therapy. [ABSTRACT FROM AUTHOR]

A series of pterostilbene- O -acetamidoalkylbenzylamines were designed, synthesized and evaluated as dual inhibitors of AChE and BuChE. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and inhibitory effects on self-induced Aβ 1 – 42 aggregation and Hu AChE-induced Aβ 1 – 40 aggregation were also tested. The results showed that most of these compounds could effectively inhibit AChE and BuChE. Particularly, compound 21d exhibited the best AChE inhibitory activity (IC 50 = 0.06 μM) and good inhibition of BuChE (IC 50 = 28.04 μM). Both the inhibition kinetic analysis and molecular modeling study revealed that these compounds showed mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. In addition to cholinesterase inhibitory activities, these compounds showed different levels of antioxidant activity. However, the inhibitory activities against self-induced and Hu AChE-induced Aβ aggregation of these new derivatives were unsatisfied. Taking into account the results of the biological evaluation, further modifications will be designed in order to increase the potency on the different targets. The results displayed in this Letter can be a new starting point for further development of multifunctional agents for Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological significance: Panax notoginseng saponins (PNS) are ingredients extracted from traditional Chinese medicinal herb Panax notoginseng. It has been demonstrated that PNS have extensive effects on the cardiovascular system, including inhibition of platelet aggregation, increasing blood flow, improving left ventricular diastolic function in hypertensive patients and anti-inflammatory effect. Aim of study: Recent researches indicated that PNS administration inhibited foam cells’ formation. The present study was designed to study the effects of PNS on atherogenesis and to explore the relevant molecular mechanisms. Materials and methods: The Zymosan A induced atherosclerosis models were used to investigate the anti-atherosclerosis effects of PNS. The integrin express array was used to check the changes of integrins. The foam cell formation was observed with transmission electron microscope. The effect of PNS on phosphorylation of FAK on threonine 397 and protein level of NF-κB was also evaluated in vitro. Results: PNS treated rats had less plaque spots on the aortas compared with Zym induced group. The formation of foam cell was inhibited by PNS. Compared with Zym treated group, the expression of most integrin families decreased except Itgav and Itgb2 after PNS treatment. PNS inhibited phosphorylation of FAK on threonine 397 and translocation of NF-κB. Conclusion: High fat diet together with Zym induces atherogenesis of rat. PNS inhibits zymosan A induced atherogenesis by suppressing FAK phosphorylation, integrins expression and NF-κB translocation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel 3-benzylidene/benzylphthalide Mannich base derivatives were synthesized. • Most compounds showed good acetylcholinesterase inhibitory activity and antioxidant effect. • Some compounds exhibited significant inhibition on self- or Cu2+-induced A β aggregation. • (Z)-13c was the outstanding representative with good multifunctional properties. • Compound (Z)-13c was more excellent than donepezil both in vitro and in vivo. To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent Ee AChE and Hu AChE inhibition (IC 50 = 9.18 × 10−5 and 6.16 × 10−4 μM, respectively), good MAO-B inhibitory activity (IC 50 = 5.88 μM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced A β 1-42 aggregation inhibitory potency, disaggregation ability on A β 1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD. [ABSTRACT FROM AUTHOR]

The combination of rifampin and pyrazinamide is commonly used in the clinical treatment of tuberculosis, but its safety needs to be further clarified. Mice were intragastric administration of rifampin 300 mg/kg, pyrazinamide 625 mg/kg, rifampin 300 mg/kg plus pyrazinamide 625 mg/kg. The results showed that rifampin significantly increased transaminases, TBIL and TBA levels in serum, increased TG, TC content, HMGCR and CYP7A1 protein, CYP7A1, FGFR4, PXR, FAS and FXR mRNA expression, but decreased the level of SREBP-1c mRNA and induced severe steatohepatitis and hepatocyte necrosis in liver in mice. While pyrazinamide can improve many abnormal indexes when it used with RFP, including liver histopathology, liver TG, TC level and serum biochemistry, GPHBP1, FAS and CYP7A1 mRNA, LPL protein expression and activity induced by rifampin. However, pyrazinamide alone significantly decreased liver TG levels and caused only slight inflammatory pathological changes in liver histopathology in mice. These data suggested that rifampin increases TG and TC levels in the liver may be related to activate HMGCR, CYP7A1, PXR and FXR, theses toxic actions of rifampin were alleviated by pyrazinamide may be due to inhibite the activity of CYP7A1, PXR and FAS, and increasing the LPL protein expression and activity. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• Phthalide alkyl tertiary amine derivatives were synthesized. • Almost all compounds displayed significant AChE inhibitory and selective activities. • Most compounds exhibited increased self-induced A β 1-42 aggregation inhibitory activity. • Compound I-8 displayed excellent BBB permeability in vitro. • Compound I-8 significantly reversed scopolamine-induced memory deficit in mice. A series of phthalide alkyl tertiary amine derivatives were designed, synthesized and evaluated as potential multi-target agents against Alzheimer's disease (AD). The results indicated that almost all the compounds displayed significant AChE inhibitory and selective activities. Besides, most of the derivatives exhibited increased self-induced A β 1-42 aggregation inhibitory activity compared to the lead compound dl -NBP, and some compounds also exerted good antioxidant activity. Specifically, compound I-8 showed the highest inhibitory potency toward AChE (IC 50 = 2.66 nM), which was significantly better than Donepezil (IC 50 = 26.4 nM). Moreover, molecular docking studies revealed that compound I-8 could bind to both the catalytic active site and peripheral anionic site of AChE. Furthermore, compound I-8 displayed excellent BBB permeability in vitro. Importantly, the step-down passive avoidance test indicated that I-8 significantly reversed scopolamine-induced memory deficit in mice. Collectively, these results suggested that I-8 might be a potent and selective AChE inhibitor for further anti-AD drug development. [ABSTRACT FROM AUTHOR]

A series of novel flurbiprofen-clioquinol hybrids were designed and synthesized as multifunctional agents for Alzheimer's disease therapy, and their potential was evaluated through various biological experiments. In vitro studies showed that most target compounds exhibited significant ability to inhibit self- and Cu2+-induced β -amyloid aggregation. Furthermore, some target compounds, especially 7i and 7r , also showed biometal chelating abilities, antioxidant activity, anti-neuroinflammatory activity and appropriate BBB permeability. These biological activities indicated that the representative compound 7i and 7r might be promising multifunctional agents for AD treatment. [ABSTRACT FROM AUTHOR]