Based on the complexity of the pathogenesis of Alzheimer's disease (AD), five biochanin A (BCA) derivatives (1-5) were designed and synthesized by using the multi-target directed ligands (MTDLs) strategy to develop multifunctional anti-AD drugs. They were obtained by introducing an alkylamine fragment into the BCA skeleton. BCA is an isoflavone from red clover with wide range of biological activities. The multifunctional anti-AD activities of 1-5 were evaluated in vitro and in vivo. The inhibitory abilities of 1-5 on cholinesterase were evaluated through enzyme inhibition experiment and molecular docking study. The results showed that the introduction of tertiary amine group enhanced the inhibitory effect of BCA on cholinesterase. Among them, 4 had the best enzyme inhibition activity with the lowest binding energy. In vitro experiments also showed that 1-5 could selectively chelate Cu2+ and had a good ability to scavenge free radicals, and inhibited A(31-42 aggregation. In vivo experiments with Caenorhabditis elegans (C. elegans), 4 showed strong ROS scavenging ability (63.7 %) and reduced A(3-aggregation ability (64.8 %). PC12 cell experiments showed that 4 was safe within the concentration range of the activity experiment, and 1-5 also had good BBB permeability. It was worth noting that single crystals of the 5-Cu(II) complex were successfully cultured and characterized by X-ray single crystal diffraction, which provided support for further structure-activity relationship analysis. Therefore, compounds 1-5, especially 4, have the potential to be promising multifunctional anti-AD compounds.

Gallic acid (GA) and berberine (BBR), the principal bioactive constituents of several traditional Chinese medicines used to treat dementia, are considered promising natural drug candidates for Alzheimer's disease (AD). Here, we reported the rational construction of GA-mediated, self-assembled BBR-metal complexes and their potential anti-AD activity. Single crystals of two complexes, BBR-Cu(I) (1) and BBR-Fe(III) (2), were successfully obtained via solvent evaporation, in which GA acted as a reductant and BBR served as the cationic moiety. Their structures were unambiguously characterized by X-ray crystallography. The resulting molecular-level structural insights suggested a metal-ion complexation pathway through which these natural compounds may synergistically exert anti-AD effects. Bioactivity assays revealed that both complexes 1 and 2 effectively scavenged reactive oxygen species, inhibited acetylcholinesterase, and prevented amyloid-(3 aggregation. We thus propose a previously unreported "reduction-assembly synergy" that exerts multifaceted effects against AD by regulating metal homeostasis. These findings provide valuable insights for the development of innovative anti-AD agents derived from natural compounds.

Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of β-amyloid and oxidative stress caused by metal dyshomeostasis are important reasons for the progression of AD. Therefore, metal therapeutics have received increasing attention. In this work, two multifunctional near-infrared porphyrin probes (1 and 2) were designed and synthesized, and the single crystals of their Cu2+ complexes (1-Cu and 2-Cu) were obtained. Comprehensive biological activity evaluations demonstrated that 1, 2 possessed strong multifunctional anti-AD activities, including metal chelating, self-/Cu2+- induced Aβ1-42 aggregation inhibition, and in vitro/in vivo reactive oxygen species (ROS) elimination. Especially after coordination with copper, the cholinesterase inhibition and ROS elimination abilities were significantly increased. Notably, X-ray single crystal diffraction of 1, 1-Cu and 2-Cu provided crucial molecular-level structural information. Combined with molecular docking, density functional theory (DFT) calculations, and molecular dynamics simulations, these crystallographic data fully elucidated the precise structure-activity relationships, revealing that the larger conjugated plane structure, differences in intermolecular forces and the picket-fence architecture significantly influenced the activities. Meanwhile, both probes exhibited highly selective fluorescence quenching responses to Cu2+ with very low cytotoxicity, indicating their promising potential as both therapeutic and diagnostic agents for AD.

Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis. Currently, there are still no drugs on the market that have a significant therapeutic effect. Zinc, an essential trace element, played a double-edged role in neuronal function—zinc deficiency accelerated cognitive decline and neurodegeneration, however overloaded zinc may cause β-amyloid (Aβ) aggregation. In contrast, the brains of AD patients exhibited significantly elevated copper concentrations around Aβ plaques, where this localized high copper concentration microenvironment catalyzed oxidative reactions and Aβ aggregation, thereby exacerbating neuronal damage. To address the interconnected pathological targets, a novel carbamate porphyrin derivative (1) and its zinc complex (1-Zn) were designed and synthesized. Single crystals of both compounds were successfully obtained and analyzed. And with further Hirshfeld surface analysis, molecular dynamics predictions and frontier molecular orbital studies, their structure characteristics and intermolecular interactions were systematically analyzed. Subsequently, metal chelation assays, antioxidant activity evaluations, Aβ aggregation inhibition assays, and anticholinesterase assays were performed to assess the multi-target therapeutic potential. Notably, 1-Zn exhibited a dual-function metal dyshomeostasis regulation ability, namely, chelating excess Cu2+ and at the same time releasing a specific amount of Zn2+ to the system. In addition, 1 and 1-Zn showed comparable ROS scavenging ability (in vitro and in vivo) and Aβ aggregation inhibition ability to the positive control drugs. 1-Zn also showed similar cholinesterase inhibition activity as rivastigmine. Consequently, this study demonstrated that 1 and 1-Zn held potential as multifunctional anti-AD agents, meriting further investigation for clinical translation.

A new multidrug crystal (MDC), composed of equimolar berberine (Ber) cation and naringenin (Nar) anion, was designed and obtained based on the compatibility of the traditional Chinese medicine (TCM) and crystal engineering technology. Crystallography, spectroscopy, Hirshfeld surface, and molecular electrostatic potential analyses revealed that the formation of Ber-Nar MDC was primarily driven by electrostatic interaction, hydrogen bond, and tc center dot center dot center dot tc stacking. Frontier molecular orbital analysis suggested that the chemical stability of Ber-Nar MDC was superior to that of the individual component. Further property assays indicated that Ber-Nar MDC not only reduced the hygroscopicity of berberine hydrochloride (Ber-Cl) to a certain extent, but also achieved sustained release of two components, and exerted synergistic effects against Alzheimer's disease. These results may promote the clinical application of naturally extracted drugs, explore new paradigms for the application of TCM combinations, and inspire the development of innovative drugs.

Considerable evidence suggests that metal ions play crucial roles in Alzheimer's disease (AD) progression, spurring the development of metal-involved therapeutic strategies. In this study, biochanin A, a bioactive ingredient derived fromTrifolium pratense L. (a traditional Chinese medicine [TCM]), was identified as a lead compound for the rational design of multifunctional metal chelators. A series of biochanin A derivatives (compounds a-e) was synthesized through a one-step carbamate introduction reaction. Their drug-likeness and pharmacokinetic profiles were assessed using an online prediction server. The bioactivities, including metal ion chelation, β-amyloid aggregation regulation, reactive oxygen species elimination, cholinesterase inhibition, and neurocytotoxicity were evaluated. The results indicated that compounds (a-e) possessed favorable pharmacokinetic profiles and potential as multifunctional metal chelators with minimal neurocytotoxicity, with compound d emerging as a particularly promising candidate. These findings may provide meaningful information for developing novel multifunctional metal chelators for AD treatment and innovative drugs derived from TCM.

Telomere with a G-quadruplex (Gq) structure is a recognized anti-tumor target. It was found that the aromatic plane of porphyrin may form π-π interactions with the Gq structure and the coordination of metal ions to porphyrin may increase its aromatic plane. Therefore, in this work, two porphyrin carbamate derivatives (1 and 2) and a Cu(II) metalloporphyrin (1-Cu) were designed and synthesized. The single crystals of 1 and 1-Cu were obtained and characteristics related to the binding interactions were analyzed at molecular level. With further Hirshfeld surface, molecular electrostatic potential, and frontier molecular orbital analyses, it was revealed that porphyrin ring, phenyl carbamate side chain and the coordinated copper ion may form synergistic binding forces with the Gq structure. Subsequently, binding ability and binding mode were tested with UV-Vis, fluorescence, and circular dichroism spectroscopies and PCR-stop method. Result showed that all three compounds selectively bound to Gq with the highest binding constant of 3.19 × 107, which was an order of magnitude higher than those to the duplex DNA. Further molecular docking and molecular dynamics simulations supported the synergistic end stacking and groove binding modes. At last, anti-tumor potentials were evaluated with cytotoxicity, cell staining, cell apoptosis, and cell migration assays. Results showed that compared with the positive control drug, the IC50 values of 1 and 1-Cu to the tumor cells were significantly lower, and their cytotoxicities to tumor cells were much higher than those to normal cells. Therefore, this work provided important information for designing novel drugs targeting Gq telomere.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive impairment. It seriously affects the health and quality of life of the elderly. It has a complex pathogenesis including β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, cholinergic neurotransmitter deficiency, metal ion dyshomeostasis, and oxidative stress, etc. Despite intensive research, there is still a lack of effective clinical drugs to treat or control AD progression. Natural products and their derivatives exhibit multi-target anti-AD effects, together with low toxicity and affordability, have emerged as promising lead compounds for drug discovery. This review summarizes the studies on anti-AD activities of natural products bearing γ-pyranone structure and their derivatives, and further discusses their structure–activity relationships (SARs), which provided a theoretical basis for the development of effective anti-AD drugs.

Multifunctional ligand design strategy may be a promising approach for the treatment of Alzheimer's disease (AD). α‐Mangostin (α‐M), a natural small molecule with anti‐AD properties, was used as the lead compound for the design and synthesis of six α‐M derivatives ( 1–6 ) with the help of computer‐aided‐drug‐design (CADD). Both theoretical calculations and experimental results suggested that 1–6 might serve as promising selective butyrylcholinesterase (BuChE) inhibitors and amyloid‐β (Aβ) aggregation inhibitors. Meanwhile, experimental results confirmed the high selectivity of the derivatives, in which 1 had the best inhibitory activity and selectivity on BuChE (IC 50 = 0.016 µM, SI = 700.63). The experimental results also showed that 1–6 could act as copper chelators and reactive oxygen species (ROS) scavengers. Furthermore, in vivo experiments with Caenorhabditis elegans also showed that 1 could scavenge ROS and inhibit Aβ aggregation. Notably, single crystals of 1 , 4 , and the 4 ‐Cu(II) complex were prepared for the first time, which provided a reliable structural basis for analyzing the structure–activity relationship. The dimethylamino derivatives ( 1 , 4 ) of α‐M showed the best activities and were expected to become promising candidate drugs for multifunctional anti‐AD.

As a natural flavonoid, apigenin (APG) has garnered considerable attention for its broad pharmacological properties. Unfortunately, the extremely poor aqueous solubility greatly restricts its clinical efficacy. Cocrystallization has been taken as an important approach to modulate physicochemical properties of parent drug. In this paper, piperazine (PIP) has been selected to assembly with APG and APG-PIP cocrystal has been successfully fabricated and characterized by single crystal X-ray diffraction and various analytical methods. Single-crystal X-ray diffraction analysis indicates APG-PIP crystallizes in the P21/c space group of monoclinic system and comprises neutral APG and PIP with the ratio of 1:1. APG and PIP are linked via O-H & sdot;& sdot;& sdot;N/N-H & sdot;& sdot;& sdot;O hydrogen bonds with a resulting 2D fes network. The 2D networks are further extended via pi & sdot;& sdot;& sdot;pi stacking interactions to afford its 3D architecture. The APG illustrates highly enhanced solubility and dissolving rate in APG-PIP cocrystal comparing with parent APG. It is notable that APG-PIP presents different equilibrium concentrations of APG along with insoluble residue when different dosages of APG-PIP are introduced. We speculate that APG and PIP may not be released equally within APG-PIP in aqueous medium due to their neutral nature and huge difference in solubility, and the existence of PIP can facilitate the dissolving of APG. This speculation has been further confirmed by investigation of relationship between equilibrium concentrations of APG and dosage of APG-PIP as well as powder dissolution experiment. The equilibrium concentrations are 0.118, 0.382, 0.556, 0.767, and 0.904 mg/mL when 5, 10, 15, 20, and 25 mg APG-PIP was put into 5 mL H2O and reveals good linear relation. The "spring and parachute" phenomenon and final similar solubility with parent APG in powder dissolution profile can be ascribed to the synergetic effect of metastable supersaturation and decreased PIP concentration due to withdrawing-replenishing operation.

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 H-1 NMR, C-13 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 beta-amyloid (A beta) 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 A beta 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 A beta 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.

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 Aβ folding. Meanwhile, in vitro experiments were carried out to investigate the anticholinesterase activity, metal chelating property, antioxidant activity, and anti-Aβ 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-Aβ aggregation ability. Among them, 4 had the strongest activity to inhibit Cu2+-induced Aβ aggregation (51.09

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The prime active ingredient of the herb curcuma longa , curcumin (CUR) has extensive pharmacological activities and high security. However, the low solubility severely restricts its investigation and application as a drug. In this paper, a new cocrystal, CUR-BPY, assembled by CUR and BPY (4,4'-bipyridine) has been synthesized and characterized by various analytical methods. Single-crystal X-ray diffraction reveals that CUR-BPY contains a pentameric BPY-CUR-BPY-CUR-BPY supramolecular architecture connected by O -H center dot center dot center dot N hydrogen bonds and further extended to give a 1D loop-like chain through aromatic interactions. Powder dissolution experiment reveals that CUR-BPY exhibits obvious spring phenomenon and about 7 times higher apparent solubility than that of raw curcumin. The improved dissolution performance should be ascribed to the careful selection of BPY coformer and expected O -H center dot center dot center dot N weak hydrogen bonding in CUR-BPY cocrystal.(c) 2023 Elsevier B.V. All rights reserved.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with complex pathogenesis. Despite the pathogenesis is unknown, the misfolding and accumulation of β-amyloid (Aβ) peptide play the important role in the occurrence and development of AD. Hence, multi-aspect intervention of the misfolded Aβ 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 Aβ by combining molecular docking simulation and molecular dynamics simulation, and evaluated the ability to intervene with the self-, Cu2+- and AChE-induced Aβ aggregation via in vitro methods. The results indicated that a–d could act as the potent multi-aspect intervention agents for Aβ aggregation. In addition, a–d could effectively eliminate peroxyl radical, had virtually no neurotoxicity, and protect cells from oxidative and Aβ-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.

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 Aβ 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.

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 β-amyloid (Aβ) 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.

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, β-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.

With the increasing aging of the population, the rational drug design for the treatment of Alzheimer's disease (AD) has become an important research area. Based on the multi-target design strategy, three coumarin derivatives 3a-3c were designed, synthesized and characterized by H-1 NMR, C-13 NMR and MS. The biological results showed that they had strong inhibition and high selectivity on acetylcholinesterase (AChE). Compound 3a had the strongest inhibitory effect on AChE (IC50 = 4.28 +/- 0.22 mu M). And all com-pounds could inhibit the self-induced and Cu2+-induced aggregation of ,B-amyloid (Al31-42), especially 3a had the best inhibitory effect on the self-aggregation of Al31-42 with the ratio of 64.27%. In addition, all compounds showed good antioxidant activity, which might be related to their hydroxyl groups. The com-pounds had good metal chelating ability, and could selectively chelate Cu2 +, Al3 +, Fe3 +, Fe2 +, and Zn2 + ions. Notably, the single crystals of 3b-Cu(II) complex [Cu-2(C17H19N2O4)2Cl2] .2CH3OH were prepared and X-ray diffracted for the first time. X-ray crystallography analysis of 3b-Cu(II) complex provided a reliable structure-activity insight about the anti-oxidative and Al31-42 disaggregation activities. Furthermore, the results of docking study were consistent with the results of in vitro experiments. 3a-3c were predicted to have good blood brain barrier permeability and ADMET properties. Overall, 3a showed the best activity and might be a promising anti-AD agent.(c) 2022 Elsevier B.V. All rights reserved.

为了应对在化学实验教学中采用内容本位语言教学(content-based language teach-ing,CBLT)模式时具有中等英语水平的中国大学生面临的挑战,本研究以行动研究的形式,通过研究人员和实践者的合作,设计了一种将翻转课堂(FC)和内容本位语言教学法整合的新型教学模式,并对其教学效果进行了初步的研究.笔者根据自己与学生的互动以及学生的反馈来反思整个教学过程,通过问卷调查收集数据,采用Excel和定性数据分析软件Nvivo进行了定性及定量分析,监测FC-CBLT教学模式的有效性.结果 表明,FC-CBLT整合模式可以成功地应用于有机化学实验课程,并且获得良好的教学效果,例如,增加了学生的参与度,加深了学生对该学科的理解等.在此基础上,笔者进一步制定了下一版整合模式设计的行动计划.