•A series of novel scutellarein-O-acetamidoalkylbenzylamines were synthesized.•Compound T-22 exhibited good acetylcholinesterase inhibitory and antioxidant activity.•Compound T-22 exhibited excellent inhibitory effects on Aβ aggregation.•Compound T-22 markedly disassembled the Cu2+-induced Aβ aggregation.•T-22 showed neuroprotective effects, low toxicity and reversed scopolamine-induced memory deficit in mice.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 Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 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 H2O2-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.Download high-res image (132KB)Download full-size image

•Novel aurone Mannich base derivatives were synthesized.•Most compounds showed good acetylcholinesterase inhibitory and antioxidant activity.•Some compounds exhibited significant inhibition of self- or Cu2+-induced Aβ aggregation.•7d and 7m were the outstanding representatives with good multifunctional properties.•Compound 7d was more excellent than donepezil and showed neuroprotective effect.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 RatAChE, EeAChE and HuAChE (IC50 = 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 H2O2-induced PC-12 cell injury. In addition, 7d also showed biometal chelating abilities, good self- and Cu2+-induced Aβ1-42 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.Download high-res image (366KB)Download full-size image

•Novel pyridoxine-resveratrol hybrids Mannich base derivatives were synthesized.•Most compounds showed dual inhibitors of AChE and MAO-B.•Compounds 7d and 8b exhibited AChE inhibition with IC50 values of 2.11 μM and 1.56 μM.•Compound 7e exhibited the highest MAO-B inhibition with an IC50 value of 2.68 μM.•All compounds displayed good antioxidant and metal-chelating properties.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 IC50 values of 2.11 μM and 1.56 μM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50 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.Download high-res image (89KB)Download full-size image

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 Cu2+-induced Aβ1–42 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 IC50 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.

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 Aβ1–42 aggregation and HuAChE-induced Aβ1–40 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 (IC50 = 0.06 μM) and good inhibition of BuChE (IC50 = 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 HuAChE-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.

•Novel scutellarein derivatives with carbon spacer-linked alkylamines were synthesized.•Compound 16d exhibited good acetylcholinesterase inhibitory and antioxidant activity.•Compound 16d exhibited excellent inhibitory effects on Aβ aggregation.•Compound 16d markedly disassembled the Cu2+-induced Aβ aggregation.•16d showed neuroprotective effects and reversed scopolamine-induced memory deficit in mice.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 Aβ1-42 aggregation, Cu2+-induced Aβ1-42 aggregation, human AChE-induced Aβ1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Aβ1-42 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 H2O2-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.A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). Compound 16d was shown to be an interesting multifunctional lead compound for AD treatment.

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 IC50 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.

•Genistein derivatives with carbon spacer-linked alkylbenzylamines were synthesized.•Most compounds exhibited good acetylcholinesterase inhibitory and antioxidant activity.•Some compounds exhibited potent inhibition Aβ aggregation.•Some compounds markedly disassembled the Cu2+-induced Aβ aggregation.•Some compounds significantly reversed scopolamine-induced memory deficit in mice.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 Aβ1–42 aggregation, Cu2+-induced Aβ1–42 aggregation, and human AChE-induced Aβ1–40 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.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). Compound 25d may be a promising multifunctional agent for AD treatment.

A facile and efficient route for the synthesis of biological activity natural product amorfrutin A was described. The key steps including tandem Michael addition–intramolecular Claisen condensation and followed by oxidative aromatization. The overall yield was about 27.2%.

•We identify a new small nonpeptidic inhibitor of integrin αvβ3, GOPPP.•GOPPP inhibits the adhesion and migration of human umbilical vein endothelial cells.•GOPPP reduces the retinal neovascularization in oxygen-induced retinopathy model.αvβ3 integrin has been reported as a promising therapeutic target for angiogenesis. In the present study, we tested the antiangiogenic activity of 3-[3-(6-guanidino-1-oxoisoindolin-2-yl) propanamido]-3-(pyridin-3-yl) propanoic acid dihydrochloride (GOPPP), a novel non-peptide αvβ3 antagonist. Both human umbilical vein endothelial cells (HUVECs) and a mouse model of oxygen-induced retinopathy (OIR) were investigated separately. HUVEC adhesion, proliferation, migration, ERK1/2 and Akt phosphorylation were assessed. C57BL/6 mice were used for the studies in the OIR model. After exposure to 75% oxygen from postnatal day (PD) 7 to PD12, the mice were returned to room air, and GOPPP was intravitreally administered on PD12. Retinal neovascularization was evaluated on PD17. Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels and ERK1/2 phosphorylation were determined by Western blot analysis of retina proteins. GOPPP significantly inhibited the pro-angiogenic effects of vitronectin on HUVECs, including adhesion, proliferation, and migration, and inhibited ERK1/2 and Akt phosphorylation. Retinal neovascularization in the OIR model was significantly suppressed by intravitreal administration of 50 ng GOPPP. The pro-angiogenic factors HIF-1α and VEGF induced by hypoxia were significantly inhibited by GOPPP in OIR mice. GOPPP administration also inhibited ERK1/2 phosphorylation in the OIR model. These results indicate that GOPPP, a novel αvβ3 integrin antagonist, may have potential for the treatment of pathological retinal angiogenesis.

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 Cu2+-induced Aβ1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50 = 0.59 ± 0.02 μM), MAO-A and MAO-B (IC50 = 1.01 ± 0.02 μM and 0.90 ± 0.01 μM respectively), excellent efficiency to block both self- and Cu2+-induced Aβ1-42 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.

A series of homoisoflavonoid Mannich base derivatives were designed, synthesized and evaluated as multifunctional agents against Alzheimer’s disease. It demonstrated that most of the derivatives were selective AChE and MAO-B dual inhibitors with good multifunctional properties. Among them, compound 10d displayed the comprehensive advantages, with excellent AChE and MAO-B inhibitory activities (IC50 = 2.49 ± 0.08 nM and 1.74 ± 0.0581 μM, respectively), good self- and Cu2+-induced Aβ1-42 aggregation inhibitory potency, antioxidant activity, biometal chelating ability and high BBB permeability. These multifunctional properties make 10d as an excellent candidate for the development of efficient drugs against AD.

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 Aβ1-42 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.

A series of 4′-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer’s disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50 = 4.91 μM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Aβ1-42 aggregation and Cu2+-induced Aβ1-42 aggregation by 89.5% and 79.7% at 25 μM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50 = 0.29 μM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer’s disease.