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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]

A series of butylphthalide and scutellarein hybrids 3-(alkyl/alkenyl) hydroxyphthalide derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease. In vitro bioactivity assays indicated that most of the compounds displayed excellent antioxidant activity and moderate to good inhibition activities of self-induced A β 1-42 aggregation. Among them, compound 7c was demonstrated as a potential and balanced multifunctional candidate displaying the best inhibitory effects on self- and Cu2+-induced A β 1–42 aggregation (90.2 % and 35.4 %, respectively) and moderate activity for disaggregation of A β 1-42 aggregation (42.5 %). In addition, 7c also displayed excellent antioxidant (2.42 Trolox equivalents), metal ions chelating, oxidative stress alleviation, neuroprotective and anti-neuroinflammatory activities. Furthermore, in vivo study demonstrated that 7c could ameliorate the learning and memory impairment induced by sodium nitrite and A β 1-42 in the step-down passive avoidance test. These balanced multifunctional profiles supporting compound 7c as a novel potential candidate for the treatment of AD. [Display omitted] • Novel 3-(alkyl/alkenyl) hydroxyphthalide derivatives were designed and synthesized. • Most compounds exhibited significant inhibition of self- and Cu2+-induced A β 1-42 aggregation. • 7c was endowed with the balanced multifunctional activities and good druggability. • 7c could ameliorate the learning and memory impairment induced by sodium nitrite and A β 1-42. [ABSTRACT FROM AUTHOR]

A series of novel chalcone derivatives was designed, synthesized and evaluated as multifunctional agents for the treatment of AD. Among of these synthesized compounds, compound TM-2 was a selective BuChE inhibitor (IC 50 = 2.6 μM) and selective MAO-B inhibitor (IC 50 = 5.3 μM), which were supported by docking study. Compound TM-2 also showed good antioxidant activity, and was a selective metal chelator, as well as a neuroprotectant. Moreover, compound TM-2 could significantly inhibit self-induced and Cu2+-induced A β 1-42 aggregation with 70.2% and 80.7% inhibition rate, respectively, and could disaggregate Cu2+-induced A β 1-42 aggregation (73.5%), the further TEM images observed provided rational explanation. Besides, compound TM-2 displayed good PAMPA-BBB permeability and conformed to the Lipinski's rule of five. Further, compound TM-2 presented precognitive effect on scopolamine-induced memory impairment in vivo assay. Therefore, compound TM-2 might be a promising multifunctional hit compound for the treatment of AD, and the further structure optimization are in progress. Image 1 • TM-2 was a selective BuChE inhibitor and selective MAO-B inhibitor. • TM-2 showed good antioxidant activity and selective metal chelator. • TM-2 could inhibit/disaggregate self/Cu2+-induced A β 1-42 aggregation. • TM-2 displayed good PAMPA-BBB permeability. • TM-2 presented precognitive effect in vivo assay. [ABSTRACT FROM AUTHOR]

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone- O -carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ 1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H 2 O 2 -induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC 50 values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC 50 values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ 1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aβ 1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization. Image 1 • Compound 5b was a reversible competition BChE inhibitor (IC 50 = 3.1 μM) and selective MAO-B inhibitor (IC 50 = 1.3 μM). • Compound 5b showed good antioxidant activity and neuroprotective effect. • Compound 5b was a selective metal chelator, and could significantly inhibit and decompose Cu2+-induced A β 1-42 aggregation. • Compound 5b could cross PAMPA-BBB and conformed to the Lipinski's rule. • Compound 5b could improve scopolamine-induced memory impairment. [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 5,6-dimethoxybenzo[ d ]isothiazol-3(2 H )-one- N -alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC 50  = 0.29 ± 0.01 μM and 0.46 ± 0.02 μM, respectively), MAO-A (IC 50  = 8.2 ± 0.08 μM and 7.9 ± 0.07 μM, respectively) and MAO-B (IC 50  = 20.1 ± 0.16 μM and 43.8 ± 2.0% at 10 μM, respectively) inhibitory activities, moderate self-induced Aβ 1–42 aggregation inhibitory potency (35.4 ± 0.42% and 48.0 ± 1.53% at 25 μM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro . Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD. [ABSTRACT FROM AUTHOR]

A series of 4′-OH-flurbiprofen-chalcone hybrids 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 hybrids exhibited good multifunctional activities. Among them, compounds 7k and 7m demonstrated the best inhibitory effects on self-induced A β 1–42 aggregation (60.0% and 78.2%, respectively) and Cu 2+ -induced A β 1–42 aggregation (52.4% and 95.0%, respectively). Moreover, these two representative compounds also exhibited good antioxidant activities, MAO inhibitions, biometal chelating abilities and anti-neuroinflammatory activities in vitro . Furthermore, compound 7m displayed appropriate blood-brain barrier permeability. These multifunctional properties highlight compound 7k and 7m as promising candidates for further development of multi-functional drugs against AD. [ABSTRACT FROM AUTHOR]

A series of scutellarein- O -acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced A β 1-42 aggregation, Cu 2+ -induced A β 1-42 aggregation, human AChE-induced A β 1-40 aggregation and disassembled Cu 2+ -induced aggregation of the well-structured A β 1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H 2 O 2 -induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD. [ABSTRACT FROM AUTHOR]

A series of novel ferulic acid- O -alkylamines derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. In vitro studies displayed that all the synthesized target compounds showed impressive inhibitory activity against butyrylcholinesterase (BuChE), significant inhibition/disaggregation of self-induced β -amyloid (A β ) aggregation and acted as potential antioxidants. Particularly, compound 7f , one of the most potent BuChE inhibitor (IC 50 value of 0.021 μM for equine serum BuChE, 8.63 μM for rat BuChE and 0.07 μM for human serum BuChE), was found to be a good acetylcholinesterase (AChE) inhibitor (IC 50 = 2.13 μM for electric eel AChE, 1.8 μM for rat AChE and 3.82 μM for human erythrocytes AChE), and the result of molecular docking provided an explanation for its selective BuChE inhibitory activity. Compound 7f also had noteworthy inhibitory effects on self-induced A β 1-42 aggregation (50.8 ± 0.82%) and was found to disaggregate self-induced A β 1-42 aggregation (38.7 ± 0.65%), which was further elucidated by the transmission electron microscopy. Meanwhile, compound 7f showed the modest antioxidant activity (0.55 eq of Trolox), good protective effect against H 2 O 2 -induced PC12 cell injury, with low toxicity. Moreover, compound 7f could cross the blood-brain barrier (BBB) in vitro . Significantly, compound 7f did not exhibit any acute toxicity in mice at doses up to 1000 mg/kg, and the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Taken together, the results indicated that compound 7f is a very promising multifunctional agent in the treatment of Alzheimer's disease, particularly the advanced stages of 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]

A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer’s disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu 2+ -induced A β 1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC 50 = 0.59 ± 0.02 μM), MAO-A and MAO-B (IC 50 = 1.01 ± 0.02 μM and 0.90 ± 0.01 μM respectively), excellent efficiency to block both self- and Cu 2+ -induced A β 1-42 aggregation (74.8 ± 1.2% and 87.7 ± 1.9% at 25 μM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD. [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 aurone Mannich base 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 with good multifunctional properties. Among them, compound 7d exhibited outstanding inhibitory activity for Rat AChE, Ee AChE and Hu AChE (IC 50 = 0.00878 ± 0.0002 μM, 0.0212 ± 0.006 μM and 0.0371 ± 0.004 μM, respectively). Moreover, 7d displayed high antioxidant activity and could confer significant neuroprotective effect against H 2 O 2 -induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu 2+ -induced A β 1-42 aggregation inhibitory potency and high BBB permeability. These multifunctional properties highlight 7d as promising candidate for further studies directed to the development of novel drugs against AD. [ABSTRACT FROM AUTHOR]

Based on previous work, a series of novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolones derivatives were identified as potential multifunctional therapeutic agents for Alzheimer's disease. Biological evaluation exhibited that these derivatives had great performance against MAO-B, A β 1-42 aggregation, oxidative stress and metal ion dyshomeostasis. Among them, 10x was selected as the optimal agent for its excellent MAO-B inhibitory activity (IC 50 = 0.41 μM, SI > 24.4), good antioxidant activity (1.16 Trolox equivalent) and anti-A β aggregation activity (56.03% and 57.51% for inhibition of self- and Cu2+-induced A β 1-42 aggregation; 81.91% and 82.40% for disaggregation of self- and Cu2+-induced A β 1-42 fibrils at 25.0 μM). Besides, 10x also exhibited obvious metal-ion chelating ability, anti-neuroinflammation (NO, TNF- α), neuroprotective activity and BBB permeability. More importantly, in vivo behavioral assessment demonstrated 10x could remarkably improve the memory and cognitive impairment in A β 1-42 induced AD mice model. Overall, these test results indicated 10x could serve as a balanced multifunctional anti-AD agent and deserved further research. [Display omitted] • Novel 5-(2-hydroxyphenyl)-2-phthalide-3(3H)-pyrazolone derivatives were synthesized. • Most compounds exhibited significant MAO-B, A β 1-42 inhibitory and antioxidant activities. • 10x was endowed with the excellent comprehensive activity and good druggability. • 10x could cross the BBB and ameliorate cognitive dysfunction on A β 1-42 -induced mice. [ABSTRACT FROM AUTHOR]

A series of 4-hydroxyl aurone derivatives were designed synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer’s disease. The results demonstrated that most of the derivatives exhibited good multifunctional properties. Among them, compound 14e displayed good inhibitory activities of self- and Cu 2+ -induced A β 1–42 aggregation with 99.2% and 84.0% at 25 μM, respectively, and high antioxidant activity with a value 1.90-fold of Trolox. In addition, 14e also showed remarkable inhibitory activities of both monoamine oxidase A and B with IC 50 values of 0.271 μM and 0.393 μM, respectively. However the 6-methoxyl aurones 15a – c revealed excellent selectivity toward MAO-B. Furthermore, the representative compounds 14e and 15b displayed good metal-chelating abilities and blood–brain barrier (BBB) permeabilities in vitro. [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]

[Display omitted] • 5,6-Dimethoxy-1-indanone-chalcone- O -carbamate 10c was a reversible hu AChE and hu BuChE inhibitor. • 10c also presented significant anti-inflammation effects, inhibition effects on A β 1-42 aggregation, and neuroprotective effect on A β 1-42 -induced PC12 cell injury. • 10c presented good metabolic stability and pharmacokinetic properties. • PET-CT imaging demonstrated that [11C] 10c could quickly penetrate the brain. • 10c could improve scopolamine-induced memory impairment. Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible hu AChE (IC 50 = 0.87 μM) and hu BuChE (IC 50 = 3.3 μM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-α production, and significantly inhibited self-mediated A β 1-42 aggregation (60.6%) and hu AChE-mediated induced A β 1-40 aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on A β 1-42 -induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [11C] 10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations. [ABSTRACT FROM AUTHOR]

A series of scutellarein- O -alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced A β 1-42 aggregation, Cu 2+ -induced A β 1-42 aggregation, human AChE-induced A β 1-40 aggregation and disassembled Cu 2+ -induced aggregation of the well-structured A β 1-42 fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H 2 O 2 -induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study. [ABSTRACT FROM AUTHOR]

A series of chromone-2-carboxamido-alkylbenzylamines were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 49 displayed excellent inhibitory potency toward acetylcholinesterase (AChE), moderate anti-oxidative activity, selective biometal chelating, and possessed good inhibitory effects on self-induced and Cu 2+ -induced Aβ aggregation. Both kinetic analysis of AChE inhibition and molecular modeling study indicated that 49 was a mixed-type inhibitor, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. These results suggested that 49 might be a potential multifunctional agent for AD treatment. [ABSTRACT FROM AUTHOR]

To discover multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed ligand strategy. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metal-chelating properties and neuroprotective effects against hydrogen peroxide induced PC12 cell injury were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good multifunctional activities. In particular, compound 15c exhibited dual inhibitory potency on acetylcholinesterase and butyrylcholinesterase with IC 50 values of 0.57 and 22.6 μM, respectively, and good antioxidative activity, with a value 1.3-fold of Trolox. In addition, 15c acted as a selective biometal chelator and possessed neuroprotective effects. Furthermore, 15c could cross the blood–brain barrier (BBB) in vitro and had significant neuroprotective effects in scopolamine-induced cognitive impairment in mice. Taken together, these results suggest that compound 15c might be a potential multifunctional agent for the treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract: A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of β-amyloid (Aβ) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Aβ 1–42 aggregation, Cu2+-induced Aβ 1–42 aggregation, and human AChE-induced Aβ 1–40 aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Aβ fibrils generated by Cu2+-induced Aβ aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment. [Copyright &y& Elsevier]

Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate A β 1-42 aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (Ee AChE, IC 50 = 0.20 μM; Hu AChE, IC 50 = 37.02 nM) and anti-A β activity (IC 50 = 1.92 μM for self-induced A β 1-42 aggregation; IC 50 = 1.80 μM for disaggregation of A β 1-42 fibrils; IC 50 = 2.18 μM for Cu2+-induced A β 1-42 aggregation; IC 50 = 1.17 μM for disaggregation of Cu2+-induced A β 1-42 fibrils; 81.7% for Hu AChE-induced A β 1-40 aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a , with suitable BBB permeability (log BB = −0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment. [Display omitted] • Novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were synthesized. • Most compounds exhibited significant AChE inhibitory and antioxidant activities. • Compound 12a was endowed with the excellent comprehensive activity and good druggability. • 12a could effectively ameliorate cognitive dysfunction on scopolamine-treated mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • 4e was a potent and well-balanced huBuChE and huMAO-B inhibitor. • 4e presented significant antioxidant, anti-inflammatory and neuroprotective effect. • 4e presented good BBB penetration and drug-like property. • 4e improved AlCl 3 -induced zebrafish AD. • 4e improved scopolamine-induced memory impairment. Herein, combining 1,2,3,4-tetrahydroisoquinoline and benzylpiperidine groups into cinnamic acid derivatives, a series of novel cinnamic acid hybrids was rationally designed, synthesized and evaluated by the multi-target-directed ligands (MTDLs) strategy. Hybrid 4e was the most promising one among these hybrids with a reversible hu BuChE inhibitor (IC 50 = 2.5 μM) and good MAO-B inhibition activity (IC 50 = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated A β 1-42 aggregation (65.2% inhibition rate). Compound 4e exhibited remarkable anti-inflammatory propery and neuroprotective effect. Furthermore, compound 4e displayed favourable blood–brain barrier penetration via parallel artificial membrane permeation assay (PAMPA). The obtained results also revealed that compound 4e significantly improved dyskinesia recovery rate and response efficiency on AD model zebrafish. Further, 4e did not show obvious acute toxicity at dose up to 1500 mg/kg in vivo and improved scopolamine-induced memory impairment. Importantly, compound 4e showed good stability in both artificial gastric fluid and artificial intestinal fluid. Therefore, compound 4e presented a promising multi-targeted active molecule for treating AD. [ABSTRACT FROM AUTHOR]

A novel series of dimethylamino chalcone- O -alkylamines derivatives was designed and synthesized as multifunctional agents for the treatment of AD. All the target compounds exhibited significant abilities to inhibit and disaggregate Aβ aggregation, and acted as potential selective AChE inhibitors, biometal chelators and selective MAO-B inhibitors. Among these compounds, compound TM-6 showed the greatest inhibitory activity against self-induced Aβ aggregation (IC50 = 0.88 μM) and well disaggregation ability toward self-induced Aβ aggregation (95.1%, 25 μM), the TEM images, molecular docking study and molecular dynamics simulations provided reasonable explanation for its high efficiency, and it was also found to be a remarkable antioxidant (ORAC-FL values of 2.1eq.), the best AChE inhibitor (IC50 = 0.13 μM) and MAO-B inhibitor (IC50 = 1.0 μM), as well as a good neuroprotectant. UV–visual spectrometry and ThT fluorescence assay revealed that compound TM-6 was not only a good biometal chelator by inhibiting Cu2+-induced Aβ aggregation (95.3%, 25 μM) but also could disassemble the well-structured Aβ fibrils (88.1%, 25 μM). Further, TM-6 could cross the blood-brain barrier (BBB) in vitro. More importantly, compound TM-6 did not show any acute toxicity in mice at doses of up to 1000 mg/kg and improved scopolamine-induced memory impairment. Taken together, these data indicated that TM-6, an excellent balanced multifunctional inhibitor, was a potential lead compound for the treatment of AD. [Display omitted] • Novel dimethylamino chalcone- O -alkylamines derivatives were rationally designed. • TM-6 was a well-balanced and promising multi-functional agent. • TM-6 showed good blood-brain-barrier permeability. • TM-6 could improve scopolamine-induced memory impairment. [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]

• 7d was a selective AChE inhibitor. • 7d was a good antioxidant agent and neuroprotectant. • 7d was a selective metal ions chelator. • 7d could inhibit self-induced, h AChE-induced and Cu2+-induced A β aggregation. • 7d could cross BBB in vitro and improved scopolamine-induced memory impairment. The multi-target-directed ligands have been regarded as the promising multifunctional agents for the treatment of Alzheimer's disease (AD). Based on our previous work, a series of genistein- O -alkylamines derivatives was developed to further explore the structure-activity-relationship. The results showed that compound 7d indicated reversible and highly selective h AChE inhibitory activity with IC 50 value of 0.53 μM. Compound 7d also displayed good antioxidant activity (ORAC = 1.1 eq.), promising neuroprotective effect and selective metal chelation property. Moreover, compound 7d significantly inhibited self-induced, h AChE-induced and Cu2+-induced A β aggregation with 39.8%, 42.1% and 74.1%, respectively, and disaggregated Cu2+-induced A β 1-42 aggregation (67.3%). In addition, compound 7d was a potential autophagy inducer and improved the levels of GPX4 protein. Furthermore, compound 7d presented good blood-brain-barrier permeability in vitro. More importantly, compound 7d did not show any acute toxicity at doses of up to 1000 mg/kg and presented good precognitive effect on scopolamine-induced memory impairment. Therefore, compound 7d was a promising multifunctional agent for the development of anti-AD drugs. [ABSTRACT FROM AUTHOR]

A novel series of O -carbamoyl ferulamide derivatives were designed by multitarget-directed ligands (MTDLs) strategy, the derivatives were synthesized and evaluated to treat Alzheimer's disease (AD). In vitro biological evaluation demonstrated that compound 4f was the best pseudo-irreversible h BChE (human butyrylcholinesterase) inhibitor with an IC 50 value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC 50 = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated A β aggregation. 4f also could reduce the levels of pathological tau and APP clearance, and displayed a wide safe range hepatotoxicity on LO2 cells. The in vivo studies revealed that 4f exhibited fascinating dyskinesia recovery rate and response efficiency on AlCl 3 -mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by A β 1-40. PET-CT imaging demonstrated that [11C] 4f exhibited high BBB penetration (especially could reach to hippocampus and striatum of brain) and had a fast brain uptake after intravenous bolus injection. Furthermore, compound 4f could improve scopolamine-induced cognitive impairment. Further, the metabolism in vitro of 4f was also investigated, and presented 3 metabolites in rat liver microsome metabolism, 4 metabolites in human liver microsome, and 4 metabolites in rat intestinal flora, providing previous data for the preclinical study. Therefore, these results implied that compound 4f was an advanced multi-function agent and deserved further preclinical study against mild-to-serve Alzheimer's disease. Image 1 • 4f was a promising multi-function agent in vitro l 4f showed fascinating dyskinesia recovery rate and response efficiency on AlCl 3 -mediated zebrafish. • 4f demonstrated significant protective effect on A β 1-40 -induced vascular injury. • PET-CT imaging revealed that [11C] 4f exhibited high BBB penetration. • 4f improved scopolamine-induced memory impairment. [ABSTRACT FROM AUTHOR]

In this work, we have developed a novel series of multi-target-directed ligands to address low levels of acetylcholine (ACh), oxidative stress, metal ion dysregulation, and the misfolded proteins. Novel apigenin-donepezil derivatives, naringenin-donepezil derivatives, genistein-donepezil derivatives and chalcone-donepezil derivatives have been synthesized, in vitro results showed that TM-4 was a reversible and potent hu AChE (IC 50 = 0.36 μM) and hu BChE (IC 50 = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced A β 1-42 aggregation (IC 50 = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate hu AChE-induced and Cu2+-induced A β aggregation. Moreover, TM-4 could activate UPS degradation pathway in HT22 cells and induce autophagy on U87 cells to clear abnormal proteins associated with AD. More importantly, TM-4 could cross BBB in vitro assay. In addition, in vivo assay revealed that TM-4 exhibited remarkable dyskinesia recovery rate and response efficiency on AlCl 3 -induced zebrafish AD model, and TM-4 indicated surprising protective effect on A β 1-40 -induced vascular injury. TM-4 presented precognitive effect on scopolamine-induced memory impairment. And the regulation of multi-targets for TM-4 were further conformed through transcriptome sequencing. More interesting, the blood, urine and feces metabolism in rat and rat/human liver microsome metabolism towards TM-4 were also investigated. Overall, TM-4 is a promising multi-function candidate for the development of drugs to Alzheimer's disease. Image 1 • TM-4 was a promising multi-function agent. • TM-4 improve AlCl 3 -induced zebrafish AD. • TM-4 protect A β 1-40 -mediated zebrafish vascular injury. • TM-4 improve scopolamine-induced memory impairment. • The transcriptome sequencing and metabolism of TM-4 were also investigated. [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]

Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible hu AChE (IC 50 = 6.8 μM) and hu BChE (IC 50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated A β 1-42 aggregation, and also inhibited h AChE-mediated induced A β 1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on A β 1-40 -mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer's disease. More interestingly, the metabolism of 3d in vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD. Image 1 • Novel apigenin-rivastigmine hybrids was rationally designed. • 3d was a promising multi-function agent. • 3d could improve AlCl 3 -induced zebrafish AD. • 3d could protect A β 1-40 -mediated zebrafish vascular injury. • 3d could improve scopolamine-induced memory impairment. [ABSTRACT FROM AUTHOR]