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Sea buckthorn (Hippophae rhamnoides L.) is an important plant with homology of medicine and food. It has rich nutritional and medicinal properties. It is used as a traditional Chinese medicine with therapeutic functions of invigorating spleen, relieving cough, eliminating food, eliminating phlegm, dispersing blood stasis, and promoting blood circulation. This review comprehensively summarized flavonoids from sea buckthorn (Hippophae rhamnoides L.), including extraction methods (solvent extraction, ultrasound-assisted extraction, microwave-assisted extraction, enzyme-assisted extraction, and collaborative extraction), two structure types (18 flavone aglycones and 81 flavone glycosides), detection methods (UV, HPLC, and NMR), bioactivities (antiviral, anti-inflammatory, hepatoprotective, weight-reducing, and hypoglycemic activities), and physiological metabolisms (most of flavonoids are converted into small molecule monophenolic acids through intestinal microbial catabolism). It will supply an important theoretical basis and valuable reference for researching and exploiting sea buckthorn (Hippophae rhamnoides L.) in the future. Practical Applications. Sea buckthorn (Hippophae rhamnoides L.) is an edible and medical plant with many functional properties. A comprehensive review on extraction, structure, detection, bioactivity, and metabolism of flavonoids from sea buckthorn (Hippophae rhamnoides L.) was made in this paper. This review will provide an important foundation for further studies of sea buckthorn (Hippophae rhamnoides L.) focusing on its development and utilization.

The fruit of Hippophae rhamnoides L. is not only used as delicious food with nutritional values, but also served as traditional Chinese medicine with multiple bioactivities.

A series of Schiff’s base derivatives was rationally designed, synthesized, and evaluated as multi-function agents for the treatment of Alzheimer’s disease (AD). The results revealed that compound 3b was a novel multifunctional agent. It acted as a highly selective monoamine oxidase-B inhibitor (IC50 = 8.4 nM), which was explained by the docking study. Compound 3b also was an antioxidant agent (2.3 eq) and could significantly inhibit self-induced Aβ1-42 aggregation (31.8%). Meanwhile, compound 3b was a selective metal chelator and could inhibit Cu2+-induced Aβ1-42 aggregation (62.3%). Furthermore, compound 3b presented good neuroprotective effects on H2O2-induced PC12 cell injury. More importantly, compound demonstrated good blood brain barrier permeability and druglike properties. Therefore, compound 3b, a promising multi-targeted active molecule, offers an attractive starting point for further study in the drug-discovery process against AD.

A new monacolin derivative, namely (1S,2S,5′R,6R,8aR)-7-hydroxy-2,6-dimethyl-8-prenyl-1,2,6,8atetrahydronaphthalene-4′,5′-dihydro-2H-pyran-1′-one (1), and five known monacolin derivatives (2–6) were separated from the highland barley Monascus purpureus Went. for the first time. Their structures were elucidated on the basis of 1D and 2D NMR, HR-ESI-MS, and relevant references. Compounds 1–6 were tested for their hypolipidemic activities by measuring the triglyceride content in HepG2 cells. Among them, compounds 1 and 2 (10 μM) exhibited moderate hypolipidemic activity.

In this study, a series of naringenin

The fruit of Hippophae rhamnoides L. has been used for centuries in Europe and Asia as a food with high nutritional and medicinal values. In this study, a bioactivity-guided phytochemical investigation of H. rhamnoides L. has resulted in four new dimethylallylated flavonolignans (1-4), four new isopropylpentenone-flavonolignan heterodimers (5-8), two new geranylated flavonolignans (9 and 10), and 14 known flavonolignan derivatives (11-24); they were elucidated by their spectrometric and spectroscopic methods, including HR-ESI-MS, NMR, IR, and UV from the fruit of H. rhamnoides L. for the first time. Among them, compounds 2, 5, 6, 20, and 21 showed potent immunosuppressive activities with IC50 values from 19.42 ± 3.91 to 48.05 ± 12.56 μM. Meanwhile, compounds 1, 4, 11, 12, and 13 showed moderate neuroprotective activities, which increased the cell survival rate from 50.30 ± 4.24% for the model group to 71.63 ± 3.04%, 70.02 ± 4.13%, 61.53 ± 5.93%, 61.08 ± 3.58%, and 65.68 ± 4.88% at 10 μM, respectively. The hypothetical biogenetic pathway and preliminary structure-activity relationship were found and discussed scientifically.

A new azaanthracene alkaloid, named 1-aza-4-(4′-hydroxybenzyl)-9,10-dimethoxydioxolobenzo-2-oxo-1,2-dihydroanthracene (1), together with seven known azaanthracene alkaloid derivatives (2–8), were isolated from Corydalis decumbens for the first time. Their structures were elucidated by their spectral data and references. Compounds 1–8 were evaluated for their antidepressive activities by inhibiting reuptake of tritiated serotonin ([3H]-NE and [3H]-5-HT) in rat brain synaptosomes. Among them, compounds 1 and 2 showed moderate antidepressive activities.

A new xanthone, named 1,3,5,9-tetrahydroxy-2-prenyl-4-(3′′ -hydroxy-3′′ -methylbutanoyl)-6,6- dimethylpyranoxanthen-10-one (1), along with five known xanthone derivatives (2–6), were isolated from Pyrethrum tatsienense for the first time. Their structures were elucidated on the basis of extensive spectroscopic analysis and references. Compounds 1–6 were screened for their hepatoprotective activities by MTT assay against D-galactosamine induced toxicities in HL-7702 cells, which revealed that compounds 1, 4, and 5 exhibited moderate hepatoprotective activities.

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, Aβ1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ1-42 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 Aβ1-42 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.

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 huAChE (IC

In this work, a series of naringenin-O-carbamate derivatives was designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD) through multi-target-directed ligands (MTDLs) strategy. The biological activity in vitro showed that compound 3c showed good antioxidant potency (ORAC = 1.0 eq), and it was a reversible huAChE (IC

Due to the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy presented the best pharmacological option for AD treatment. Herein, a series of novel 2-acetylphenol-O-alkylhydroxyethylamine derivatives was rationally designed and synthesized. Of these derivatives, 5c was a good multifunctional agent (eeAChE IC50 =7.9 μM, MAO-B IC50 = 9.9 μM, BACE1 IC50 = 8.3 μM) in vitro and displayed a mixed-type AChE inhibition, which could bind to the CAS and PAS of AChE. Compound 5c also exhibited good antioxidant activity (ORAC = 2.5 eq) and neuroprotective effects. Furthermore, compound 5c was a selective metal ions chelator. And it could cross blood-brain barrier in vitro and complied with drug-like properties rule of 5. Therefore, compound 5c was a promising multifunctional agent for the treatment of AD.

Alzheimer's disease is a chronic and progressive brain neurodegenerative disease affecting over 30 million people globally. Currently, no effective treatment is available due to multiple factors involved in the progression of AD. Given that the numerous AD-related targets in the disease network, the multi-target-directed ligands (MTDLs) strategy are considered as the promising strategy to treat AD. Herein, the multi-target compounds with/without ChEs are in clinical and in progress are reviewed. To further characterize the drug-likeness, and ADME properties are calculated using the Qikprop. This review will provide highlights for the treatment of AD.

To discover multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of indanone–chalcone hybrid compounds were designed and synthesized based on the multitarget-directed ligand strategy. Their monoamino oxidases (MAO-A and MAO-B) and Aβ1–42 aggregation inhibitory activities were evaluated. The results were shown that all synthetic compounds exhibited mostly good multifunctional activities. Among all, compound TM-11 represented the best Aβ1–42 aggregation inhibitory potency (IC50 ~1.8 μM) and good disaggregation activity (IC50 ~7.9 μM). Both TEM images and docking studies provided good reasonable explanation to the hypothesis. Meanwhile, compound TM-11 was a selective MAO-B inhibitor, as well as a neuroprotective agent against Aβ1–42-induced toxicity. Based on the structural considerations, the lipophilicity of the compound TM-11 could render to pass through blood−brain barrier (BBB) in vitro in accordance with the Lipinski’s rule of five. In conclusion, these results were suggested that compound TM-11 might be a potential multifunctional agent for the treatment of AD.

Three new phenanthraquinones (1–3), together with seven known phenanthraquinone derivatives (4–10) were isolated from Heleocharis dulcis for the first time. Their structures were established on extensive NMR, MS, UV, IR experiments in conjunction with their references. Compounds (1–10) were evaluated for their hypolipidemic activities for the first time. Compounds 1, 3, 7, and 9 (10 μM) exhibited significant hypolipidemic activities by measuring the triglyceride content in HepG2 cells with simvastatin as positive control. The chemotaxonomic significance of compounds (1–10) was also discussed.

A new aurone, named (Z)-4,5-methylenedioxy-6-hydroxybenzene-2[(2′,3′,4′-trimethoxy)-2-methyl-2(4-methyl-3-penten-1-yl)-2H-1-benzopyran-5-yl)methylene]-3-benzofuranon (1), and nine known aurones (2–10) were isolated from Sophora japonica L. for the first time. Compounds 1–10 were evaluated for their neuroprotective activities against 6-OHDA-induced cell death in SH-SY5Y cells. Compounds 1, 3, 8, and 10 exhibited significant neuroprotective activities with IC50 values in the range of 2.89–6.02 μM.

A simple, rapid, sensitive, selective and label-free method is presented for the colorimetric determination of lincomycin (Lin) by using HAuCl4 and NaOH. Upon the addition of Lin, the mixture of HAuCl4 and NaOH shows a color change from colorless to blue (or dark blue). The limit of colorimetric detection is as low as 1 μM, observed both in Milli-Q water and real samples. The selectivity of Lin detection is excellent compared with 9 other common antibiotics. On the basis of the “three-color” principle of Thomas Young, we extracted the red, green and blue (RGB) alterations of the sensor in the absence and presence of different concentrations of Lin. The color changes are quantitatively illustrated by the total Euclidean distances (EDs = [ΔR2 + ΔG2 + ΔB2]1/2). The good linear relationship between the EDs and Lin concentration is used for the quantitative assay of Lin. The developed method demonstrates great potential for the detection of Lin in environmental water and milk.

A novel series of ferulic acid derivatives was designed and synthesized on the basis of the multi-target-directed ligands strategy for the treatment of Alzheimer's disease (AD). In vitro results revealed that all the target compounds were highly effective and selective butyrylcholinesterase (BuChE) inhibitors. In particular, compound TM-10 showed the best BuChE inhibitory activity, with IC50 = 8.9 nM, and remarkable monoamine oxidase A and B inhibitory potency, with IC50 = 6.3 and 8.6 μM, respectively. TM-10 could inhibit (53.9%) and disaggregate (43.8%) self-induced amyloid-β peptide (Aβ) aggregation. In addition, TM-10 exhibited potent antioxidant activity (ORAC = 0.52 equiv) and neuroprotective effect against Aβ1-42-mediated SH-SY5Y neurotoxicity, and it acted as an autophagic activator. TM-10 also showed good blood-brain barrier penetration. Furthermore, TM-10 exhibited a favorable dyskinesia recovery rate and response efficiency on an AlCl3-induced zebrafish AD model and a potent neuroprotective effect on Aβ1-40-induced zebrafish vascular injury. Further, in vivo assays demonstrated that TM-10 showed low acute toxicity, and the step-down passive avoidance test indicated that this compound could improve scopolamine-induced memory deficit in mice. Therefore, the present study displays evidence that TM-10 is a potent, multi-functional agent against AD and could be a promising lead candidate for anti-Alzheimer's disease drug development.

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 huBuChE inhibitor (IC50 = 2.5 μM) and good MAO-B inhibition activity (IC50 = 1.3 μM) and antioxidant potency (ORAC = 0.4 eq). Moreover, compound 4e significantly inhibited self-mediated Aβ1-42 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.

The fruit of Citrus medica L. var. sarcodactylis Swingle is a functional food with rich nutrients and medicinal values because of its content of bioactive compounds. A bioactivity-guided chemical investigation from the fruits of C. medica L. var. sarcodactylis Swingle afforded three new benzodioxane neolignans (1–3), three new phenanthrofuran neolignan glycosides (4–6), two new biphenyl-ketone neolignans (7–8), two new 1′,7′-bilignan neolignans (9–10), as well as fourteen known neolignan derivatives (11–24), which were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. These neolignan derivatives were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, IR spectral data and compared with the data described in the literature. Among them, compounds 1–3 and 12–13 exhibited moderate hepatoprotective activities to improve the survival rates of HepG2 cells from 46.26 ± 1.90% (APAP, 10 mM) to 67.23 ± 4.25%, 62.87 ± 4.43%, 60.06 ± 6.34%, 56.75 ± 2.30%, 58.35 ± 6.14%, respectively. Additionally, compounds 7–8 and 21–22 displayed moderate neuroprotective activities to raise the survival rates of PC12 cells from 55.30 ± 2.25% to 66.94 ± 3.37%, 70.98 ± 5.05%, 64.64 ± 1.93%, and 62.81 ± 4.11% at 10 μM, respectively. The plausible biogenetic pathway and preliminary structure–activity relationship of the selected compounds were scientifically summarized and discussed in this paper.

Two new lignans, 3,4-(10-methoxy-phenylallyl)-9″-((10'-isopropanol-3',4'-furan)-phenylacetyl)-8″-dioxane-7″-O

Cucumis bisexualis has been widely served as a beneficial wild fruit in China. Four new homoisoflavonoids (1-4), together with eight known homoisoflavonoid derivatives (5-12) were isolated from the 90% EtOH extract of C. bisexualis, using repeated open column chromatography and preparative thin-layer chromatography. They were elucidated based on the analysis of spectral data and references from the fruits of C. bisexualis for the first time. These compounds (1-12) were evaluated for their in vitro inhibitory effects against the increase of aspartate aminotransferase and alanine aminotransferase levels in H2 O2 -induced HepG2 cells in the range of their maximum nontoxic concentration. Among them, compounds 3, 4, 8, and 9 exhibited certain hepatoprotective activities. PRACTICAL APPLICATIONS: Cucumis bisexualis A.M. Lu ＆ G.C. Wang is an edible and medical fruit with many functional properties. A detailed study was made to identify the bioactive constituents of C. bisexualis and four new homoisoflavonoids (1-4) and eight known homoisoflavonoid derivatives (5-12) were isolated from the fruits of C. bisexualis for the first time. Compounds 3, 4, 8, and 9 exhibited certain hepatoprotective activities. This study suggests that natural compounds isolated from C. bisexualis could be used as promising hepatoprotective agents.

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 hBChE (human butyrylcholinesterase) inhibitor with an IC50 value of 0.97 μM 4f was a potent selective MAO-B (monoamine oxidase-B) inhibitor (IC50 = 5.3 μM), and could inhibit (58.2%) and disaggregate (43.3%) self-mediated Aβ 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 AlCl3-mediated zebrafish, and demonstrated significant protective effect on vascular injury caused by Aβ1-40. 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.

Ethnopharmacological relevance The flower of Hosta plantaginea (Lam.) Aschers (Liliaceae) is a traditional medicinal material in Mongolian medicine for treating sore throat, hoarseness, pulmonary fever, and toxic fever in folk. The present work investigated anti-prostate cancer and hepatoprotective activities of flavonoid derivatives from H. plantaginea (Lam.) Aschers. Aim of the study: To isolate and identify the chemicals of H. plantaginea (Lam.) Aschers for anti-prostate cancer and hepatoprotective activities. Materials and methods Active chemicals were isolated and purified from H. plantaginea (Lam.) Aschers by chromatographic methods, and their structures were established on spectroscopic analysis and references. These compounds were evaluated for their anti-prostate cancer activities using the LNCaP prostate cancer cells, and assayed for their hepatoprotective activities on CCl4-induced injury of human L-O2 cells, respectively. Results Four new flavonol-lignan heterodimers (1–4), together with nine known flavonoid derivatives (5–13) were isolated from this plant for the first time. Among them, some compounds exhibited moderate anti-prostate cancer and hepatoprotective activities. Conclusion Compounds 1, 2, 5, and 6 showed anti-prostate cancer activities using the LNCaP prostate cancer cells with IC50 values of 17.84, 33.26, 54.13, and 81.55 μg/mL, and compounds 3, 4, 8, and 9 exhibited moderate hepatoprotective activities, respectively. A preliminary structure-activity relation was summarized in this paper.

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 huAChE (IC50 = 0.36 μM) and huBChE (IC50 = 15.3 μM) inhibitor, and showed potent antioxidant activity (ORAC = 1.2 eq). TM-4 could significantly inhibit self-induced Aβ1-42 aggregation (IC50 = 3.7 μM). TM-4 was also an ideal neuroprotectant, potential metal chelation agent, and it could inhibit and disaggregate huAChE-induced and Cu2+-induced Aβ 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 AlCl3-induced zebrafish AD model, and TM-4 indicated surprising protective effect on Aβ1-40-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.

Phytochemical study of the EtOAc fraction (active extract) of the fruits of Ulmus pumila L. resulted in the isolation of thirteen flavane derivatives, and they were identified by their precise spectral data and literature. All the compounds (1-13) were obtained from the fruits of U. pumila L. for the first time. Meanwhile, the compounds (1-13) were assayed for their hepatoprotective and neuroprotective activities, respectively. Compounds 1, 2, 5, 7 and 8 (10μM) exhibited remarkable hepatoprotective activities, and compounds 9, 10, and 13 showed significant neuroprotective activities with IC50 values of 4.08, 5.34, and 2.02μM, respectively.

A general approach is presented for synthesis of multicolored gold nanoparticles (GNPs) by Au(I)-mediated generation of interlocking rings in proteins and antibiotics. The Au(I) ions are shuttled from proteins to antibiotics, and this causes the formation of interlocking rings. The multicolored GNPs of different sizes were synthesized in the rings by using the rapid nucleation method. To take the unique colors of GNPs, a functional array was designed for the colorimetric determination and discrimination of antibiotics, specifically of amoxicillin, chlortetracycline, erythromycin, spiramycin, neomycin, thiamphenicol, gentamycin and lincomycin. The method is based on the "three color" (RGB) principle. The color response patterns are characteristic for each antibiotic and can be quantitatively differentiated by statistical techniques. The limits of detection (LOD, at S/N = 3) for spiramycin (Sp) have been calculated to be 0.18 μM and 0.10 μM in water and milk, respectively. The good linear range (from 0.3 to 3.5 μM) has been used for the quantitative assay of Sp in a certified reference material. Graphical abstractSchematic presentation of gold nanoparticles (GNPs) synthesis via formation of interlocking rings in protein and antibiotics. The Au(I) ions mediate protein and antibiotics to be interlocking rings, which are quickly fixed via microwave reaction. The GNPs are synthesized and assembled in the rings.

Bioactivity-guided phytochemical investigation of Cucumis bisexualis has led to the isolation of three new coumarin-aurone heterodimers (1-3), along with six aurone derivatives (4-9) were isolated from C. bisexualis for the first time. Their structures were determined by their extensive spectroscopic data and comparison with the values reported in the references. All isolated compounds (1-9) were evaluated for their hepatoprotective activities on human L-O2 cells, which compared with positive control of Bifendatatum. Among them, compounds 1, 2, and 7 exhibited moderate hepatoprotective activities to promote effects on the proliferation of L-O2 cells.

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 huAChE (IC50 = 6.8 μM) and huBChE (IC50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aβ1-42 aggregation, and also inhibited hAChE-mediated induced Aβ1-40 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 Aβ1-40-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.

The fruit of Citrus medica L. var. sarcodactylis Swingle is not only used as a traditional medicinal plant, but also served as a delicious food. Six new (3′→7″)-biflavonoids (1–6), and twelve known biflavonoid derivatives (7–18) were isolated and characterized from the fruits of C. medica L. var. sarcodactylis Swingle for the first time. Their structures were determined by extensive and comprehensive analyzing NMR, HR-ESI-MS, UV, and IR spectral data coupled with the data described in the literature. Compounds (1–18) were evaluated for their hypolipidemic activities with Orlistat as the positive control, and assayed for their immunosuppressive activities with Dexamethasone as the positive control, respectively. Among them, compounds (1–3) exhibited moderate inhibition of pancreatic lipase activity by inhibiting 68.56 ± 1.40%, 56.18 ± 1.57%, 53.51 ± 1.59% of pancreatic lipase activities at the concentration of 100 μM, respectively. Compounds (4–6) and 8 showed potent immunosuppressive activities with the IC50 values from 16.83 ± 1.32 to 50.90 ± 1.79 μM. The plausible biogenetic pathway and preliminary structure activity relationship of the selected compounds were scientifically summarized and discussed in this study.

A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer’s disease (AD). The results showed that compound TM - 9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B ( hu AChE, hu BuChE, and hu MAO-B with IC 50 values of 1.2 μM, 3.8 μM and 2.6 μM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM - 9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM - 9 abided by Lipinski’s rule of five. Furthermore, our investigation proved that TM - 9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro . The results suggest that compound TM - 9 , an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer’s disease.

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.

A cobalt/copper-cocatalyzed facile synthesis of imidazo[1,2-a:3,4-a']dipyridiniums from 2H-[1,2'-bipyridin]-2-ones and 2-bromoacetophenones is presented. This strategy provides an alternative to the imidazo[1,2-a:3,4-a']dipyridinium synthesis by employing readily available substrates and a simple procedure, which would render this method potentially useful in organic synthesis.

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.

A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56μM, 2.3μM, 0.3μM and 1.4μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski's rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.