Metabolomics analysis of Ligustri Lucidi Fructus at different harvest times during the whole growing period based on ultra-high-performance liquid chromatography with mass spectrometry.

After medicinal market research, it was found that the harvest time of Ligustri Lucidi Fructus (LLF) was chaotic in practice. In order to determine the optimal harvest period of LLF to ensure its pharmacological activity, metabolomics analysis of LLF at different harvest times based on ultra-high-performance liquid chromatography-triple quadrupole-(linear ion trap)-tandem mass spectrometry was established. In this study, 166 differential metabolites (DMs) in 448 metabolites at different harvest times were screened out based on variable importance in projection value, and among them, 94 DMs with regular trends of change in relative content (59 increased and 35 decreased with the growth period) were chosen to further research. The result of the multivariate statistical analysis showed that November was the optimal harvest period of LLF. Additionally, 10-hydroxyligustroside, oleoside 11-methyl ester, and salidroside were screened out to be used as the evaluation indicators of immature LLF, while specnuezhenide, nuezhenoside G13, and neonuezhenide were the evaluation indicators of mature LLF. This study provides fundamental insight for metabolite identification and proposes the best harvest period of LLF to avoid confusion in the medicinal market.

Design and synthesis of ligustrazine derivatives as potential anti-Alzheimer's agents.

A novel series of ligustrazine derivatives was designed, synthesized, and evaluated as acetylcholinesterase (AChE) and butylcholinesterase (BuChE) inhibitors for the treatment of Alzheimer's disease (AD). In vitro studies displayed that some of the synthesized compounds revealed promising AChE and BuChE inhibitory effects. Particularly, compounds E12 and E27, indicated highly AChE inhibitory activity with IC50 values of 1.85 µM and 0.98 µM, respectively and showed noteworthy protective effects against on glutamate-induced SH-SY5Y cells damage at 1 µM and 10 µM concentrations. Furthermore, molecular simulation docking elucidates compounds E12 and E27 interacting with residues in the binding site of AChE (PDB code: 4EY7) and BuChE (PDB code: 1P0I), emphasizing the protein residues that participate in the main interactions with the two targets. Taken together, these results revealed that compounds E12 and E27 might be potential lead compounds for further structure optimization in the drug-discovery process against AD.

Simultaneous determination and quality evaluation of 16 compounds in Ligustri Lucidi Fructus covering different regions and processed products using ultra-high-performance liquid chromatography-mass spectrometry.

A quantitative analysis method and a chemical pattern recognition method were developed to evaluate raw Ligustri Lucidi Fructus (LLF) from different regions and different processed products. In this study, a comprehensive strategy using ultra-high-performance liquid chromatography-mass spectrometry quantitative analysis method was established for the simultaneous determination of 16 components in 47 batches of LLF covering 19 regions belonging to 8 provinces and 24 batches of different processed products (steamed LLF without auxiliary material, wine-steamed LLF, salt-steamed LLF, and vinegar-steamed LLF). The results of this study indicated that the proposed method was reliable and accurate for the rapid analysis proved by detection limit, quantification limit, precision, and accuracy. Furthermore, principal component analysis and hierarchical cluster analysis were employed to analyze the experimental data, showing that the best-quality samples of 47 batches of raw LLF were S47 (Lantian, Shaanxi), S39 (Pingyang-2, Shandong), S38 (Pingyang-1, Shandong), and S45 (Lingbao, Henan), whereas the worst-quality samples were S7-S16 (Huzhou, Zhejiang). In 24 batches of processed products, the best-quality samples were S48 (salt steamed 2 h), S60 (wine steamed 2 h), and S61 (wine steamed 4 h). Meanwhile, the heat map showed that the contents of triterpenoid saponins, including C16 (ursolic acid), C15 (oleanic acid), and C14 (maslinic acid), were higher than those of other compounds in 71 batches of samples. These results suggested that the quality of raw LLF in the central and northern regions was better than that in the southern regions, and regarding the processed products, different auxiliary materials had little effect on the quality of LLF, but steaming time of 2 h was appropriate. Briefly, this study proposed a multiparameter quantitative analysis method for the overall quality control of raw LLF samples covering different regions in China and different processed LLF.

Review of bioactivity and structure-activity relationship on baicalein (5,6,7-trihydroxyflavone) and wogonin (5,7-dihydroxy-8-methoxyflavone) derivatives: Structural modifications inspired from flavonoids in Scutellaria baicalensis.

Baicalein (5,6,7-trihydroxyflavone) and wogonin (5,7-dihydroxy-8-methoxyflavone), as typical flavonoids isolated from Scutellaria baicalensis, are well important precursors in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Researches in medicinal chemistry field have synthesized baicalein and wogonin derivatives with multiple medicinal properties including antitumor, central nervous system (CNS), anti-inflammatory, antiviral, antimicrobial and hypoglycemic activities. Simultaneously, SAR (Structure-Activity Relationship) analysis has been gradually possessed, along with a great deal of derivatives have been derived for potential targets. In this article, we comprehensively summarize the biological activities and SAR for baicalein and wogonin derivatives, along with the featuring bioactive molecules reported in patents, wishing to provide an overall retrospect and prospect on baicalein and wogonin analogues.

[Virtual screening and antiepileptic activity evaluation of COX-2 inhibitory components in Trachelospermi Caulisetfolium].

This study investigated the potential active components against cyclooxygenase-2(COX-2) from Trachelospermi Caulisetfolium and explored the pharmacodynamic material basis.A pharmacophore-based virtual screening method was adopted to establish a COX-2 ligands-based HipHop pharmacophore model on the basis of the information on compounds with COX-2 inhibitory activity reported in published research articles.The reported components in Trachelospermi Caulisetfolium were collected to establish the compound library and matched with the pharmacophores.Subsequently, the matched small molecule compounds underwent molecular docking with COX-2 targets(PDB ID: 3 LN1), and the interaction of potential active monomers and COX-2 was further explored by molecular dynamics.The antiepileptic effect of active monomer arctigenin(15) was determined based on the pentylenetetrazole(PTZ)-induced seizure model, and its modulatory effect on the COX-2 level was evaluated.A compound library containing 118 chemical constituents in Trachelospermi Caulisetfolium was established by literature retrieval.The preferred pharmacophore 04 was selected through test set verification for virtual screening of the compound library of Trachelospermi Caulisetfolium.After matching, six potential constituents with COX-2 inhibitory activity were obtained.The interaction of five compounds with COX-2 and COX-1 was analyzed by molecular docking, and 10 ns molecular dynamics was performed on two compounds.Compound 15 could prolong the latent time of PTZ-induced seizures at medium and high doses, improve the anxiety-and depression-like behaviors induced by PTZ, reduce the expression level of COX-2, and decrease the number of COX-2 immuno-posi-tive cells in the hippocampal CA1 region.The results showed that it was reasonable to investigate the components in Trachelospermi Caulisetfolium with COX-2 inhibitory activity based on virtual screening and activity evaluation.

Advances in Anti-Osteoporosis Polysaccharides Derived from Medicinal Herbs and Other Edible Substances.

Osteoporosis is a common metabolic bone disease, and treatment is required for the prevention of low bone mass, deterioration of microstructural bone tissue, and fragility fractures. Osteoporosis therapy includes calcium, vitamin D, and drugs with antiresorptive or anabolic action on the bone. Therapy for osteoporosis does not include taking non-steroidal anti-inflammatory drugs (NSAID), but pain associated with osteoporotic fractures can be treated by taking non-steroidal anti-inflammatory drugs (NSAID). Recently, polysaccharides extracted from medicinal herbs and edible substances (PsMHES) have attracted attention on account of their safety and promising anti-osteoporosis effects, whereas a systematic review about their potential in anti-osteoporosis is vacant to date. Herein, we reviewed the recent progress of PsMHES with anti-osteoporosis activities, looking to introduce the advances in the various pharmacological mechanisms and targets involved in the anti-osteoporosis effects, extraction methods, main mechanism involved in Wnt/[Formula: see text]-catenin pathways and RANKL (Receptor Activator for NF[Formula: see text]B ligand or TNFSF25) pathways, and Structure-Activity Relationships (SAR) analysis of PsMHES. Typical herbs likeAchyranthes bidentate and Morinda officinalis used for the treatment of osteoporosis are introduced; their traditional uses in traditional Chinese medicine (TCM) are discussed in this paper as well. This review will help to the recognition of the value of PsMHES in anti-osteoporosis and provide guidance for the research and development of new anti-osteoporosis agents in clinic.

Research progress in biological activities of succinimide derivatives.

Succinimides are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Researches in medicinal chemistry field have isolated and synthesized succinimide derivatives with multiple medicinal properties including anticonvulsant, anti-inflammatory, antitumor and antimicrobial agents, 5-HT receptor ligands and enzyme inhibitors. Simultaneously, SAR (Structure-Activity Relationship) analysis has been gradually possessed, along with a great deal of derivatives have been derived for potential targets. In this article, we comprehensively summarize the biological activities and SAR for succinimide derivatives, along with the featuring bioactive molecules reported in patents, wishing to provide an overall retrospect and prospect on the succinimide analogues.

Research progress in biological activities of isochroman derivatives.

Isochromans are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Medicinal chemistry investigators have synthesized drug-like isochroman candidates with multiple medicinal features including central nervous system (CNS), antioxidant, antimicrobial, antihypertensive, antitumor and anti-inflammatory agents. Simultaneously, SAR (Structure-Activity Relationship) analysis has drawn attentions among medicinal chemists, along with a great deal of derivatives have been derived for potential targets. In this article, we thoroughly summarize the biological activities and part of typical SAR for isochroman derivatives reported on existing literatures and patents, wishing to provide an overall retrospect and prospect on the isochroman analogues.

Passiflora edulis: An Insight Into Current Researches on Phytochemistry and Pharmacology.

Passiflora edulis, also known as passion fruit, is widely distributed in tropical and subtropical areas of the world and becomes popular because of balanced nutrition and health benefits. Currently, more than 110 phytochemical constituents have been found and identified from the different plant parts of P. edulis in which flavonoids and triterpenoids held the biggest share. Various extracts, fruit juice and isolated compounds showed a wide range of health effects and biological activities such as antioxidant, anti-hypertensive, anti-tumor, antidiabetic, hypolipidemic activities, and so forth. Daily consumption of passion fruit at common doses is non-toxic and safe. P. edulis has great potential development and the vast future application for this economically important crop worldwide, and it is in great demand as a fresh product or a formula for food, health care products or medicines. This mini-review aims to provide systematically reorganized information on physiochemical features, nutritional benefits, biological activities, toxicity, and potential applications of leaves, stems, fruits, and peels of P. edulis.

[Virtual screen of effective AChE inhibitory constituents from Glycyrrhizae Radix et Rhizoma based on pharmacophore and molecular docking].

This research is to predict anti-Alzheimer's disease active constituents on the target of acetylcholinesterase(AChE) from Glycyrrhizae Radix et Rhizoma with the help of pharmacophore and molecular docking. AChE ligand-based pharmacophore model was set up and the molecular library of the constituents from Glycyrrhizae Radix et Rhizoma were established by collecting literature. Then the constituents from Glycyrrhizae Radix et Rhizoma were screen for the potential AChE inhibitory potency in silico through matching with the best pharmacophore model. The flexible docking was used to evaluate the interactions between compounds screened from pharmacophore model and AChE protein(PDB ID:4 EY7). The interactions were expressed including but not limited to CDOCKER interaction energy, hydrogen bonds and non-bonding interactions. The molecular library of Glycyrrhizae Radix et Rhizoma contains 44 chemical constituents. As for the pharmacophore model, six kinds of potential AChE inhibitory constituents from Glycyrrhizae Radix et Rhizoma were considered to be the promising compounds according to the results of searching 3 D database of pharmacophore model. The molecular docking was possessed and the interaction patterns were given to show the detail interactions. The compounds screening from the pharmacophore model were consistent with the existing studies to some degree, indicating that the virtual screen protocols of AChE inhibitory constituents from Glycyrrhizae Radix et Rhizoma based on pharmacophore and molecular docking was reliable.

A Review of Traditional Uses, Phytochemistry, and Pharmacological Properties of the Genus Saururus.

The genus Saururus, belonging to Saururaceae, contains two species, S. cernuus L. and S. chinensis (Lour) Baill. with common utilization in traditional medicine from Asia to North America for the treatment of edema, beriberi, jaundice, leucorrhea, urinary tract infections, hypertension, hepatitis diseases, and tumors. An extensive review of literature was made on traditional uses, phytochemistry, and ethnopharmacology of Saururus using ethno-botanical books, published articles, and electronic databases. The 147 of chemical constituents have been isolated and identified from S. cernuus and S. chinensis, and lignans, flavonoids, alkaloids, anthraquinones, saponins, and phenols are the major constituents. Various pharmacological investigations in many in vitro and in vivo models have revealed the potential of the genus Saururus with anti-inflammatory, antitumor, anti-oxidant, hepatoprotective, antimelanogenic, lipid-lowering, and bone protective activities, supporting the rationale behind numerous of its traditional uses. Due to the noteworthy pharmacological properties, Saururus can be a better option for new drug discovery. Data regarding many aspects of this plant such as toxicology, pharmacokinetics, quality-control measures, and the clinical value of the active compounds is still limited which call for additional studies.

Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect.

The pyrazolone structural motif is a critical element of drugs aimed at different biological end-points. Medicinal chemistry researches have synthesized drug-like pyrazolone candidates with several medicinal features including antimicrobial, antitumor, CNS (central nervous system) effect, anti-inflammatory activities and so on. Meanwhile, SAR (Structure-Activity Relationship) investigations have drawn attentions among medicinal chemists, along with a plenty of analogues have been derived for multiple targets. In this review, we comprehensively summarize the biological activity and SAR for pyrazolone analogues, wishing to give an overall retrospect and prospect on the pyrazolone derivatives.

Rhodomyrtus tomentosa (Aiton.): A review of phytochemistry, pharmacology and industrial applications research progress.

Rhodomyrtus tomentosa (Aiton) is a flowering plant native to southern and southeastern Asia. Up to date, 106 chemical constituents have been isolated and identified from R. tomentosa. Among these compounds, triterpenoids, flavonoids, phenols and meroterpenoids are the major constituents. Investigations of pharmacological activities of R. tomentosa revealed that this edible medicinal herb exhibits a wide range of therapeutic potential including antibacterial, antitumor, anti-inflammatory and antioxidant activities both in vivo and in vitro. The purpose of this review is to provide an overview of R. tomentosa studies until 2019. This article also intends to review advances in the botanical, phytochemical, pharmacological studies and industrial applications of R. tomentosa, which will provide a useful bibliography for further investigations and applications of R. tomentosa in medicines and foods.

Challenges Faced with Small Molecular Modulators of Potassium Current Channel Isoform Kv1.5.

The voltage-gated potassium channel Kv1.5, which mediates the cardiac ultra-rapid delayed-rectifier (IKur) current in human cells, has a crucial role in atrial fibrillation. Therefore, the design of selective Kv1.5 modulators is essential for the treatment of pathophysiological conditions involving Kv1.5 activity. This review summarizes the progress of molecular structures and the functionality of different types of Kv1.5 modulators, with a focus on clinical cardiovascular drugs and a number of active natural products, through a summarization of 96 compounds currently widely used. Furthermore, we also discuss the contributions of Kv1.5 and the regulation of the structure-activity relationship (SAR) of synthetic Kv1.5 inhibitors in human pathophysiology. SAR analysis is regarded as a useful strategy in structural elucidation, as it relates to the characteristics that improve compounds targeting Kv1.5. Herein, we present previous studies regarding the structural, pharmacological, and SAR information of the Kv1.5 modulator, through which we can assist in identifying and designing potent and specific Kv1.5 inhibitors in the treatment of diseases involving Kv1.5 activity.

The Crucial Role of CXCL8 and Its Receptors in Colorectal Liver Metastasis.

CXCL8 (also known as IL-8) can produce different biological effects by binding to its receptors: CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC). CXCL8 and its receptors are associated with the development of various tumor types, especially colorectal cancer and its liver metastases. In addition to promoting angiogenesis, proliferation, invasion, migration, and the survival of colorectal cancer (CRC) cells, CXCL8 and its receptors have also been known to induce the epithelial-mesenchymal transition (EMT) of CRC cells, to help them to escape host immunosurveillance as well as to enhance resistance to anoikis, which promotes the formation of circulating tumor cells (CTCs) and their colonization of distant organs. In this paper, we will review the established roles of CXCL8 signaling in CRC and discuss the possible strategies of targeting CXCL8 signaling for overcoming CRC drug resistance and cancer progression, including direct targeting of CXCL8/CXCR1/2 or indirect targeting through the inhibition of CXCL8-CXCR1/2 signaling.

Actinidia chinensis Planch.: A Review of Chemistry and Pharmacology.

Actinidia chinensis Planch. (A. chinensis), commonly known as Chinese kiwifruit, is a China native fruit, which becomes increasingly popular due to attractive economic, nutritional, and health benefits properties. The whole plant including fruits, leaves, vines, and roots of A. chinensis are used mainly as food or additive in food products and as folk medicine in China. It is a good source of triterpenoids, polyphenols, vitamin C, carbohydrate, amino acid, and minerals. These constituents render the A. chinensis with a wide range of pharmacological properties including antitumor, antioxidant, anti-inflammatory, immunoregulatory, hypolipemic, antidiabetic, and cardiovascular protective activities, suggesting that it may possibly be value in the prevention and treatment of pathologies associated to cancer, oxidative stress, and aging. This minireview provides a brief knowledge about the recent advances in chemistry, biological activities, utilization, and storage of Chinese kiwifruit. Future research directions on how to better use of this crop are suggested.

Synthesis and anti-tyrosinase mechanism of the substituted vanillyl cinnamate analogues.

This study aimed to synthesize and screen tyrosinase inhibitors for delay fruit browning. A series of vanillyl cinnamate analogues were designed and synthesized by simple processes, and the inhibitory effects of all the synthesized derivatives on mushroom tyrosinase were evaluated. In the enzymatic activity test, compounds 21, 22, and 26 had significant (P < 0.05) effect on mushroom tyrosinase at a preliminary screening dose (1 mg/mL in vitro). IC50 analysis showed that the IC50 values of compounds 21, 22 and 26 were 268.5 µM, 213.2 µM and 413.5 µM, respectively. In the cytotoxicity evaluation, Cell Counting Kit-8 (CCK-8) assay showed that compounds 21, 22 and 26 had no significant effect on the proliferation of hepatocyte L02 and B16 melanoma cells at the dosage of 25-200 µM. Inhibition of tyrosinase activity and melanin content in B16 melanoma cells investigations indicated that compounds 21, 22 and 26 inhibited both cellular tyrosinase activity and melanin content dose-dependently and more strongly than the reference standard arbutin. The UV-visible spectra showed compound 22 inhibits the formation of dopamine quinone, further the molecular docking analysis of compound 22 with tyrosinase (PDB: 2Y9X) indicated that compound 22 interacted with the amino acid residues of tyrosinase. The results of anti-browning test showed that compounds 21, 22 and 26 had significant tyrosinase inhibition and anti-browning effects on fresh-cut apple slices at 4 °C in 48 h. Compound 22 could be used as novel tyrosinase inhibitor to delay fruit browning.

Polygala tenuifolia-Acori tatarinowii herbal pair as an inspiration for substituted cinnamic α-asaronol esters: Design, synthesis, anticonvulsant activity, and inhibition of lactate dehydrogenase study.

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1ß2γ2 GABAA receptors (EC50 46.3 ±â€¯7.3 µM). Thus, 68-70 were promising candidates for developing into anti-epileptic drugs, especially for treatment of refractory epilepsies such as Dravet syndrome.

Excavating precursors from the traditional Chinese herb Polygala tenuifolia and Gastrodia elata: Synthesis, anticonvulsant activity evaluation of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives.

Epilepsy is a group of neurological disorders characterized by recurrent seizures that disturbs about 60 million people worldwide. In this article, a novel series of 3,4,5-trimethoxycinnamic acid (TMCA) ester derivatives 1-35 were designed inspired from the traditional Chinese herb pair drugs Polygala tenuifolia and Gastrodia elata and synthesized followed by in vivo and in silico evaluation of their anticonvulsant potential. All the synthesized derivatives were biologically evaluated for their anticonvulsant potential using two acute model of seizures induced in mice, the maximal electroshock (MES) and sc-pentylenetetrazole (PTZ) models. Simultaneously, the motor impairment as a surrogate of acute neurotoxicity and in vitro screening of cytotoxicity against HepG-2 cells line were assessed through the rotarod performance test and CCK-8 assay, respectively. In addition, the physicochemical and pharmacokinetic parameters of the active compounds were determined. Our results showed that compounds 5, 7, 8, 13, 20, 25, 28, 30 and 32 exhibited preferable anticonvulsant activity in primary evaluation, with compounds 28 and 32 being the most promising anticonvulsant agents in according to results of subsequent pharmacology and toxicity evaluation. Additionally, the molecular modeling experiments predicted good binding interactions of part of the obtained active molecules with the gamma-aminobutyric acid (GABA) transferas. Therefore, it could be concluded that the synthesized derivatives 28 and 32 would represent useful lead compounds for further investigation in the development of anticonvulsant agents.

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives.

TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.