Study of multifunctional anti-AD ligands: design, synthesis, X-ray crystal structure and biological evaluation of diosmetin derivatives.

The development of anti-AD drugs has attracted much attention as the number of AD patients is increasing year by year. Five diosmetin derivatives (1-5) were designed and synthesized by introducing carbamate groups. The crystal structure of 1 was analyzed by X-ray diffraction, which showed a large conjugated coplanar structure and might be favorable for the insertion into the Aß folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Aß aggregation ability of 1-5. The results showed that 1-5 had good cholinesterase inhibitory activities. Compound 4 showed the highest inhibitory activities against butyrylcholinesterase (IC50 = 0.0760 µM). Further kinetic experiments and molecular docking studies showed that 4 could bind well to butyrylcholinesterase. The molecular dynamics simulations also signified that compared with diosmetin, 4 could reduce the flexibility of the butyrylcholinesterase protein skeleton to a greater extent, and thus had a better inhibitory effect. In addition, 1-5 could selectively chelate copper ions and all of them had good antioxidant activity as well as anti-Aß aggregation ability. Among them, 4 had the strongest activity to inhibit Cu2+-induced Aß aggregation (51.09%) and had low cytotoxicity. In addition, in vivo ROS activity assay (Caenorhabditis elegans) showed that 4 had the ability to scavenge ROS. Besides, the in vivo Aß aggregation assay showed that 4 could reduce Aß aggregation. In conclusion, 4 has the potential to be developed into a multifunctional anti-AD drug.

Chemical composition analysis of Qingyan dropping pills using ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

RATIONALE: This study developed a method for the rapid classification and identification of the chemical composition of Qingyan dropping pills (QDP) to provide the theoretical basis and data foundation for further in-depth research on the pharmacological substance basis of the formula and the selection of quality control indexes. METHODS: Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and data postprocessing technology were used to analyze the chemical composition of QDP. The fragmentation information on possible characteristic fragments and related neutral losses was summarized based on the literature and was compared with the MS data obtained from the assay, and thus a rapid classification and identification of chemical components in QDP could be achieved. RESULTS: A total of 73 compounds were identified, namely 24 flavonoids, 14 terpenoids, 30 organic acids and their esters, 3 alkaloids, and 2 phenylpropanoids. CONCLUSIONS: In this study, UHPLC-Q-TOF-MS and data postprocessing technology were used to realize the rapid classification and identification of the chemical constituents of QDP, which provided a comprehensive, efficient, and fast qualitative analysis method, a basis for further quality control and safe medication of QDP.

Diosmetin derivatives as multifunctional anti-AD ligands: Design, synthesis, and biological evaluation.

With the increasing aging population, rational design of drugs for Alzheimer's disease (AD) treatment has become an important research area. Based on the multifunctional design strategy, four diosmetin derivatives (1-4) were designed, synthesized, and characterized by 1H NMR, 13C NMR, and MS. Docking study was firstly applied to substantiate the design strategies and then the biological activities including cholinesterase inhibition, metal chelation, antioxidation and ß-amyloid (Aß) aggregation inhibition in vitro were evaluated. The results showed that 1-4 had good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition, metal chelation (selective chelation of Cu2+ ions), antioxidation, self-induced, Cu2+-induced, and AChE-induced Aß aggregation inhibition activities, and suitable blood-brain barrier (BBB) permeability. Especially, compound 3 had the strongest inhibitory effect on AChE (10-8 M magnitude) and BuChE (10-7 M magnitude) and showed the best inhibition on AChE-induced Aß aggregation with 66.14% inhibition ratio. Furthermore, compound 3 could also reduce intracellular reactive oxygen species (ROS) levels in Caenorhabditis elegans and had lower cytotoxicity. In summary, 3 might be considered as a potential multifunctional anti-AD ligand.

A coumarin-based multifunctional chemosensor for Cu2+/Al3+ as an AD theranostic agent: Synthesis, X-ray single crystal analysis and activity study.

The pathogenesis of Alzheimer's disease (AD) is complex. So far there is no effective drug to treat the disease. The pathological changes of AD began 30 years before symptoms, so early diagnosis is considered to be important for AD treatment. Integrating diagnosis and therapy into a single regent has provided a new opportunity for AD treatment. Given that metal dyshomeostasis is thought to be one of the key factors to cause AD, a Schiff base substituted coumarin (probe 1) has been designed and synthesized as a selective metal chelator for multi-factor anti-AD in this work. The results of metal ions recognition showed that probe 1 had high selective fluorescent turn-on response to Al3+ and fluorescent turn-off response to Cu2+, due to intramolecular charge transfer (ICT) mechanism. Meanwhile, the results of both in vitro and in vivo bioactivities evaluation including metal chelation, reactive oxide species (ROS) elimination, self-/Cu2+-induced Aß aggregation showed that 1 and 1-Cu(II) complex had excellent synergistic anti-AD activities. In addition, 1 had low cytotoxicity and was predicted to cross the blood-brain barrier (BBB). Noticeably, X-ray single crystal diffraction of 1-Cu(II) provided molecular level information to explain the structure and theranostic activity relationship. To sum up, 1 may be a promising candidate for the development of AD theranostic agent.

Emodin derivatives as promising multi-aspect intervention agents for amyloid aggregation: molecular docking/dynamics simulation, bioactivities evaluation, and cytoprotection.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of ß-amyloid (Aß) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Aß peptides aggregation is a promising therapy for AD. In previous work, we obtained the emodin derivatives (a-d) with multifunctional anti-AD activities, including metal ions chelation, cholinesterase inhibition, and hydroxyl/superoxide anion radical elimination. In this work, we predicted the interaction of emodin derivatives (a-d) with Aß by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu2+- and AChE-induced Aß aggregation via in vitro methods. The results indicated that a-d could act as the potent multi-aspect intervention agents for Aß aggregation. In addition, a-d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Aß-induced damage. The prediction results of ADMET properties showed that a-d had suitable pharmacokinetic characteristics. It suggested that a-d could act as the promising multi-targeted directed ligands (MTDLs) for AD. These results may provide meaningful information for the development of the potential MTDLs for AD which are modified from natural-origin scaffolds.

A Review on the Natural Components Applied as Lead Compounds for Potential Multi-target Anti-AD Theranostic Agents.

Alzheimer's disease (AD) is a neurodegenerative disease that seriously affects the health and quality of life of the elderly. Its pathogenesis is very complex and there is still a lack of effective clinical drugs to treat or control the development of AD. Studies have shown that ß-amyloid (Aß) deposition, tau protein hyperphosphorylation, reduced levels of brain cholinergic transmitters, and oxidative stress are the main causes of AD. Furthermore, recent studies showed that metal dyshomeostasis could relate to all the above pathogenesis of AD and was a key factor in the development of AD. Natural compounds and their derivatives have multi-target therapeutic effects on AD, and they also have the advantages of low toxicity, and low cost, which are important directions for anti- AD drugs. Meanwhile, early detection may play an important role in preventing the development of AD. The concept of "theranostic agent" combining molecular imaging probes and therapeutic drugs has emerged in recent years. Fluorescence imaging has been widely studied and applied because of its non-invasive, high resolution, high sensitivity, rapid imaging, and low cost. However, at present, most of the research methods in this field use individual therapeutic or diagnostic reagents, which is not conducive to exploring the optimal treatment time window and drug efficacy. Therefore, this work reviewed the natural compounds and their derivatives which all have been studied for both the in vitro and in vivo therapeutic and diagnostic anti-AD activities. At last, structure and activity relationship (SAR) was discussed and potential AD theranostic natural agents were put forwarded to provide a more detailed theoretical basis for the further development of drugs with diagnostic and therapeutic effects in AD.

Carrier-free Chinese herbal small molecules self-assembly with 3D-porous crystal framework as a synergistic anti-AD agent.

Alzheimer's disease (AD) is a devastating neurodegenerative disease caused by multiple factors. Single-target drugs have limited efficacy for AD treatment. Therefore, multi-target intervention strategy has great potential. Traditional Chinese medicine (TCM) is mostly used in the form of compound prescription, which has the polypharmacology behavior. Rhizoma Coptidis and Radix et Rhizoma Rhei are frequently used as the couplet medicines of TCM for AD therapy. In this study, the novel carrier-free nanoassembly with 3D-porous frame crystal structure has formulated from supramolecular self-assembly of berberine (BER) and rhein (RHE), the main active components of Rhizoma Coptidis and Radix et Rhizoma Rhei, respectively. Combining with the spectral data and single crystal structure, the self-assembly process was clarified as dominated by electrostatic interaction and π-π stacking. In vitro release property, cholinesterase (ChE) inhibition, ß-amyloid (Aß) aggregation regulation, radical elimination, metal ions chelation and cytotoxicity assay indicated that the obtained BER-RHE assembly had the Fickian diffusion-controlled sustained release ability, synergistic biological activities and virtually no neurotoxicity. In addition, in vivo reactive oxygen species (ROS) level evaluation showed that the assembly could reduce the accumulation of intracellular ROS in Caenorhabditis elegans (C. elegans). Meanwhile, BER-RHE assembly could also be used as a novel potential carrier for drug delivery due to its superior 3D-porous frame. This green and facile strategy for carrier-free nanoassembly microscopic construction via supramolecular self-assembly might provide inspiration for the development of multi-target therapy for AD and the design of the novel drug delivery system.

Synthesis, single crystal characterization and anti-AD activities of a novel complex of Cu(II) with in situ formed protonated chrysin derivative ligand.

Alzheimer's disease (AD), the most common form of neurodegeneration disorder in adults, is becoming the overwhelming burden on the healthcare and economic system. In this study, chrysin derivative with the morpholine moiety was designed, synthesized and evaluated based on the multi targets directed ligands strategy for the treatment of AD centered with therapeutic attempts to restore metal homeostasis. It selectively coordinated with the important bio-metal ions related AD, especially Cu2+. Notably, single crystals of both 1 and 1-Cu(II) were obtained and the single crystal structures were characterized by X-ray crystal diffraction, which provided a basis to further explore the possible structure-activity relationship at the molecular level. Compound 1 and 1-Cu(II) complex showed potent anti-oxidative activities, with respect to both ·OH and ·O2- scavenging properties In addition, 1 had good inhibitory activity on Aß1-42 aggregation, and it could target copper dyshomeostasis through extracting Cu2+ from the amyloids. The studies in silico showed that 1 had brain availability and peroral bioavailability. Taken together, compound 1, as the derivative of chrysin, might be a promising advanced lead candidate for the development of new anti-AD drugs and it may provide a useful template for studying the structure-activity relationships of biometal-coordinating drugs.

Study on Multi-Target Synergistic Treatment of Alzheimer's Disease Based on Metal Chelators.

Alzheimer's disease (AD) has become the fourth leading cause of death in the world. Due to its complex pathogenesis, there is still a lack of effective drug treatments. Studies have found that the metal dyshomeostasis is closely related to other pathogeneses of AD such as oxidative stress, ß-amyloid protein deposits, etc. Therefore, it becomes an important target to find the appropriate metal chelating agents to regulate the metal homeostasis. At the same time, because of the complex pathogenesis, single target drugs cannot achieve good effects. Therefore, current studies are mainly focused on exploring multi-target therapy for AD. In this work, the multi-target studies based on metal chelators and other targets with synergistic anti-AD activities were reviewed. The structural characteristics of different chelating agents were summarized and the structure-activity relationship was analyzed, which provided some valuable clues for the subsequent development of anti-AD multi-target drugs based on metal chelating agents.

A multifunctional metal regulator as the potential theranostic agent: Design, synthesis, anti-AD activities and metallic ion sensing properties.

Although there is no cure for Alzheimer's disease (AD) due to its complex pathogenesis, early detection and treatment can help delay the development of the disease. So, it is necessary to develop multifunctional metal regulators that can integrate the therapeutics and diagnostics effect against AD. In this work, N-(anthracene-9-ylmethylene)benzohydrazide (probe 1), a fluorescent probe with imine and carbonyl as chelating sites was designed and synthesized. Results showed that 1 had good activities related to AD, such as regulation of metal homeostasis, inhibition of ß-amyloid (Aß) aggregation and scavenging of reactive oxygen species. The selectivity experiment showed that probe 1 had a good recognition effect on Cu2+. Fluorescence imaging assay also indicated that probe 1 had a good fluorescence imaging effect on Cu2+ in living cells. Furthermore, probe 1 had showed no cytotoxicity and good BBB permeability. These results indicated that probe 1 had potential diagnostic and therapeutic capabilities, and can be used as the multifunctional theranostic agent for AD.

A multifunctional anti-AD approach: Design, synthesis, X-ray crystal structure, biological evaluation and molecular docking of chrysin derivatives.

With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by 1H NMR, 13C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Aß1-42 aggregation (self-, Cu2+-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu2+, Fe2+, Zn2+ and Al3+ ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(C19H18NO4)2] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aß1-42 disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.

Effect of Bis-Dimethylamine Substitution on DNA Binding Property and Cytotoxic Activity of Polyhydroxyxanthone.

A bis-dimethylamine substituted xanthone (Xan-2) was obtained by cationic modification of the free C3 and C6 hydroxy groups of 1,3,6-trihydroxyxanthone (Xan-1) which was isolated from Polygala hongkongensis Hemsl.. The results of the spectroscopic analysis, melting profiles, electrophoretic migration, PCR assay and molecular docking indicated that the hydrophobic plane of Xan-1 and Xan-2 could intercalate into the DNA base pairs meanwhile the basic amine alkyl chain of Xan-2 could bind with DNA phosphate framework via electrostatic interaction. Thus, Xan-2 exhibited higher DNA binding affinity than Xan-1. Further study showed that Xan-2 could inhibit the proliferation of HeLa, SGC-7901 and A549 cells effectively by MTT assay and induce apoptosis of HeLa cells as detected by AO/EB staining and flow cytometry assay. Interestingly, Xan-2 exhibited selective cytotoxicity to cells, which was proved by its relatively low inhibitory effect on Raw 264.7 cell. What these studies mean is that disubstituted amine alkyl chains will play an important role in DNA binding property and cytotoxic activity, providing a direction for the development of novel potential antitumor agents.

Multifunctional fluorescence sensor as a potential theranostic agent against Alzheimer's disease.

Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). Metal dyshomeostasis, ß-amyloid (Aß) accumulation and oxidative stress, etc. are related to metal ions. So, metal therapeutics has aroused increasingly more attention, especially the research of metal-involved theranostic agents. In this work, a highly selective and sensitive multifunctional fluorescence sensor 1 with a naphthol unit based on photoinduced electron transfer (PET) and excited state proton transfer (ESPT) mechanism was synthesized, and its synergistic biological effects on regulating metal dyshomeostasis, modulating Aß accumulation and scavenging reactive oxygen species (ROS) was evaluated. The results demonstrated that 1 exhibited significant fluorescence enhancement towards Al3+ (the limit was as low as 0.01 ppm), superior chelating abilities with metal ions, even better modulation effect of Cu2+-induced Aß1-42 accumulation than curcumin, good elimination effect of ROS, clear fluorescence image in living cells, low cytotoxic and appropriate blood brain barrier (BBB) permeability. Overall, these findings revealed that 1 could be used as a potential theranostic agent against AD for further research.

Design, synthesis and biological evaluation of naringenin carbamate derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

A series of naringenin derivatives were designed and synthesized as multifunctional anti-Alzheimer's disease (AD) agents. The results showed that these derivatives displayed moderate-to-good acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities at the micromolar range (IC50, 12.91 ~ 62.52 µM for AChE and 0.094 ~ 13.72 µM for BuChE). Specifically, compound 1 showed the highest inhibitory activity against BuChE with the IC50 value of (0.094 ± 0.0054) µM. A Lineweaver-Burk plot and molecular docking studies demonstrated that 1 targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of BuChE. Besides, all derivatives showed excellent hydroxyl free radicals (·OH) scavenging ability than vitamin C and cyclic voltammetry results displayed that 1 could effectively scavenge superoxide anion radical (·O2-). In addition, compound 1 displayed good metal chelating properties and had anti-Aß aggregation activities. Therefore, compound 1 might be the potential anti-AD agent for further developments.

Novel chrysin derivatives as hidden multifunctional agents for anti-Alzheimer's disease: design, synthesis and in vitro evaluation.

Alzheimer's disease (AD) is the most common type of dementia, the exact etiology of the disease has not been known yet. The use of single-target drugs limits the efficacy of drugs and has certain side effects. In this study, the 'hidden' multi-target strategy was used in combination with chrysin's metal chelating site and rivastigmine's anti-cholinesterase pharmacophore to form an ester, which improves the hydrophobicity and protects the phenolic hydroxyl group at the same time. Four derivatives (1-4) were synthesized as the hidden multifunctional agents for AD therapy. Most of the compounds displayed good activities of anti-cholinesterase, antioxidant, appropriate blood brain barrier (BBB) penetration and certain inhibitory activity of ß-amyloid (Aß) aggregation. Compound 3 was demonstrated as the highest selective butyrylcholinesterase (BuChE) inhibitor and targeted both the catalytic active site (CAS) and the peripheral anion site (PAS). And it could be hydrolyzed by BuChE to release chrysin with good ability to chelate Cu2+ and Fe2+. At the same time, phenol fragment can exert its good antioxidant effect. Overall, these findings demonstrated that compound 3 might be considered as a potential hidden multifunctional candidate in the therapy of AD.

A review on α-mangostin as a potential multi-target-directed ligand for Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive memory loss, declining language skills and other cognitive disorders. AD has brought great mental and economic burden to patients, families and society. However due to the complexity of AD's pathology, drugs developed for the treatment of AD often fail in clinical or experimental trials. The main problems of current anti-AD drugs are low efficacy due to mono-target method or side effects, especially high hepatotoxicity. To tackle these two main problems, multi-target-directed ligand (MTDL) based on "one molecule, multiple targets" has been studied. MTDLs can regulate multiple biological targets at the same time, so it has shown higher efficacy, better safety. As a natural active small molecule, α-mangostin (α-M) has shown potential multi-factor anti-AD activities in a series of studies, furthermore it also has a certain hepatoprotective effect. The good availability of α-M also provides support for its application in clinical research. In this work, multiple activities of α-M related to AD therapy were reviewed, which included anti-cholinesterase, anti-amyloid-cascade, anti-inflammation, anti-oxidative stress, low toxicity, hepatoprotective effects and drug formulation. It shows that α-M is a promising candidate for the treatment of AD.

Design, Synthesis and Biological Evaluation of Xanthone Derivatives for Possible Treatment of Alzheimer's Disease Based on Multi-Target Strategy.

Four xanthone derivatives were synthesized and evaluated as acetylcholinesterase inhibitors (AChEIs) with metal chelating ability and antioxidant ability against Alzheimer's disease (AD). Most of them exhibited potential acetylcholinesterase (AChE), butylcholinesterase (BuChE) inhibitory, antioxidant and metal chelating properties. Among them, 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one had the highest ability to inhibit AChE and displayed high selectivity towards AChE (IC50 =2.403±0.002 µM for AChE and IC50 =31.221±0.002 µM for BuChE), and it was also a good antioxidant (IC50 =2.662±0.003 µM). Enzyme kinetic studies showed that this compound was a mixed-type inhibitor, which could interact simultaneously with the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE. Interestingly, its copper complex showed more significant inhibitory activity for AChE (IC50 =0.934±0.002 µM) and antioxidant activity (IC50 =1.064±0.003 µM). Molecular dockings were carried out for the four xanthone derivatives in order to further investigate the binding modes. Finally, the blood-brain barrier (BBB) penetration prediction indicated that all compounds might penetrate BBB. These results suggested that 1-hydroxy-3-[2-(pyrrolidin-1-yl)ethoxy]-9H-xanthen-9-one was promising AChEI with metal chelating ability and antioxidant ability for the further investigation.

Design, synthesis and anti-Alzheimer's disease activity study of xanthone derivatives based on multi-target strategy.

A series of xanthone derivatives were designed, synthesized and evaluated as multifunctional ligands against Alzheimer's disease (AD). In vitro studies showed all xanthone derivatives had good metal chelating property and exhibited selective inhibitory activity against Acetylcholinesterase (AChE). In particular, compound 2a showed the highest inhibitory activity against AChE, and the IC50 value was (0.328 ± 0.001) µM, which was comparable to tacrine. Kinetic analysis and molecular docking studies indicated that these derivatives targeted both the catalytically active site (CAS) and the peripheral anion site (PAS) of AChE. Moreover, all derivatives showed higher anti-oxidative activity than vitamin C. Furthermore, copper complex had higher anti-AChE activity and antioxidant activity. Thus, these xanthone derivatives are potential multi-targeted-directed ligands for further development for the treatment of AD.

Zinc(II)-Mediated Carbene Insertion into C-H Bonds in Alkanes.

The cationic zinc adduct {[HB(3,5-(CF3)2Pz)3]Zn(NCMe)2}ClO4 catalyzes the functionalization of tertiary, secondary, and primary C-H bonds of alkanes via carbene insertion. Ethyl diazoacetate serves as the :CHCO2Et carbene precursor. The counteranion, supporting ligand, and coordinating solvents affect the catalytic activity. An in situ generated {[HB(3,5-(CF3)2Pz)3]Zn}(+) species containing a bulkier {B[3,5-(CF3)2C6H3]4}(-) anion gives the best results among the zinc catalysts used.