Design, synthesis and anti-rheumatoid arthritis activity of target TLR4 inhibitors.

A series of 1-(2-oxocyclohexyl)butane-1, 3-dione derivatives were designed and synthesized as TLR4 inhibitors by modifying the core structure of the lead compound ((6, 8-dioxo-1, 2, 3, 4, 6, 7, 8, 8a-octahydronaphthalen-2-yl) carbamate)). In vitro, compound 3p significantly inhibited the proliferation of rat synovial cells, inhibited the proliferation of LPS-induced RAW264.7 cells, and inhibited TLR4 activity, with IC50 values of 1.21 ± 0.09 µM, 0.73 ± 0.05 µM and 0.43 ± 0.03 µM, respectively, which was superior to the positive control methotrexate. In vivo anti-rheumatoid arthritis evaluation, compound 3p can significantly inhibit the inflammatory factors TNF-α, IL-1ß and IL-6, so as to achieve the therapeutic purpose. In the preliminary mechanism study, compound 3p has obvious regulatory effects on the abnormal increase of TLR4, JAK2 and STAT3 protein and gene expression related to inflammatory signaling pathway in RAW264.7 cells. In summary, this study aims to develop more effective candidates for rheumatoid arthritis.

The Inhibitory Activity of Natural Products to Xanthine Oxidase.

The natural products have a new chemical structure and biological active diversity, so they are favored by scientific researchers. Gout is a high incidence and high-risk disease, and the current treatments are not satisfactory. Xanthine oxidase (XO) is a key enzyme responsible for the development and progression of various metabolic and oxidative stress-related diseases. Excessive activity of XO leads to elevated serum urate levels, which in turn leads to the development of hyperuricemia. This review mainly introduces the recent progress of the new research on the anti-gout activity of natural products that could provide new treatment methods for gout and information for the discovery and development of new anti-gout drugs.

Synthesis, activity and mechanism for double-ring conjugated enones.

The relationship between TLR4 and inflammation-related diseases has been paid more and more attention. The studies have shown that TLR4/NF-κB signaling pathway plays an important role in the transmission of inflammatory signals. A large number of pro-inflammatory factors, chemokines, adhesion factors, TLR4 and its ligands interact with each other, and jointly promote the development of diseases. In this work, 8 target compounds were synthesized to screen the inhibitory activity of TLR4 in vitro. The results of TLR4 inhibition test in vitro showed that the double-ring conjugated enones had a good inhibitory activity, and the IC50 value of compound 4f was 0.56 ± 0.10 µM, and it was superior to the positive control methotrexate. To further study the anti-inflammatory effect and mechanism of double-ring conjugated enones by using LPS induced rat synovial cell inflammation model. The results of the mechanism test showed that compound 4f could effectively promote the apoptosis of rat synovial cells, and the mechanism might be related to the up-regulation of the expression of apoptosis-related protein Caspase-3. In addition, compound 4f could significantly inhibit the increase of inflammatory factors TNF-α, IL-1ß and IL-6 in rat synovial cells induced by LPS, showing a good anti-inflammatory activity. In the TLR4/NF-κB signaling pathway test of rat synovial cells, compound 4f can effectively regulate the expression levels of TLR4, MyD88, NF-κB and IκB related proteins in TLR4/NF-κB signaling pathway, which may be due to its inhibition of LPS-induced inflammation in rat synovial cells. At the same time, it inhibits the abnormal proliferation of cells and its important mechanism promoted of apoptosis.

Synthesis and anti-tumor activity of marine alkaloids.

Marine alkaloids were divided into five categories from the perspective of anti-tumor activity. The optimization process, chemical synthesis, anti-tumor activity evaluation and structure-activity relationship of various compounds were discussed.

Preparations and antioxidant activities of sesamol and it's derivatives.

Antioxidants is a kind of substances that can effectively inhibit the oxidation reaction of free radicals. There are many chemical components with antioxidant activity in natural products. Sesamol is one of the natural products with antioxidant activity, and it is often used as an antioxidant in food, medicine and other fields. In the present study, sesame was used as the extraction raw material for the extraction and separated of sesamol with antioxidant activity. On this basis, a total 10 of sesamol derivatives were synthesized by two steps reaction with sesamol as starting material. The antioxidant activity of these sesamol derivatives were tested, and the test results showed that these sesamol derivatives had a good antioxidant activity, among them, compound 4d had the best antioxidant activity. Sesamol derivatives can be used as an antioxidant in food, medicine and other fields and it needs a further study.

Design, synthesis and anti-rheumatoid arthritis evaluation of double-ring conjugated enones.

Four series of double-ring conjugated enones were designed, synthesized and studied for the inhibition of synovial cell activity through the modification of Dysodensiol K core structure, double-ring, double-bond and double-carbonyl groups. For in vitro synovial cell assay of rats, compound 151 and 168 exhibited good inhibitory activities, with IC50 values of 2.71 ± 0.18 and 2.68 ± 0.16 µM respectively. At the same time, the LDH release and LD50 test results revealed that the target compounds were low cytotoxicity and acute toxicity. For in vivo CIA model test through the oral administration, compounds 151 and 168 were exhibited similar effect to positive control group methotrexate.

Design, synthesis and biological evaluation of novel 7H-benzo [c] [1, 3] dioxolo [4, 5-f] chromen-7-one derivatives with potential anti-tumor activity.

In this study, a series of novel 7H-benzo [c] [1,3] dioxolo [4, 5-f] chromen-7-one derivatives were obtained by structural modification of the lead compounds with Fissitungfine B. A total 15 compounds were designed, synthesized and evaluated as inhibitors of tumor. These target compounds have the novel chemical structures that named three six-membered rings including one lactone six-membered ring. In vitro assay, the results showed that the target compounds have a broad spectrum and strong of anti-tumor activity. Such as the target compound 4n to MCF-7 was IC50 = 0.35 ± 0.01 µM, to A-549 was IC50 = 0.37 ± 0.01 µM, to Hela was IC50 = 0.56 ± 0.02 µM, to MDC-803 was IC50 = 0.53 ± 0.02 µM and COLO-205 was IC50 = 0.50 ± 0.02 µM in vitro. At the same time, in vivo anti-tumor activity assay results showed that the target compounds had a good inhibitory effect on tumor growth. Among them, the target compound 4n had the best anti-tumor activity, it could inhibit tumor growth well at a low dose. The target compound 4n could be used as a candidate drug for further research and development, in order to be used as early as application in the clinical treatment of tumors.

Design, synthesis and biological activity of a novel ethylenediamine derivatives as H1 receptor antagonists.

In this study, a series of novel ethylenediamine compounds were obtained by structural modification of the lead compounds with thonzylamine, and using the principle of modifying by bioisostere formation and modification with alkyl groups. In vitro assay, the biological activities showed that the target compounds have good properties in inhibiting mast cell degranulation and releasing histamine and ß-aminohexidase, such as the compounds 5c, 5g, 5k, 5l and 5o, especially of compound 5k to mast cell degranulation is IC50 = 0.0106 ±â€¯0.001 µmol⋅L-1, histamine release was IC50 = 0.0192 ±â€¯0.005 µmol⋅L-1 and ß-hexosaminidase release was IC50 = 0.0455 ±â€¯0.002 µmol⋅L-1in vitro. At the same time, in vivo biological activities assay results showed that have a good Histamie induce bronchospasm effect with relatively long duration and good protective effect in vivo, among which the protective effect of compound 5k was 79.74 ±â€¯0.30%, compounds 5c, 5g, 5k, 5l and 5o could inhibit the capillary permeability of increasing which were caused by histamine.

Macular hole retinal detachment after intravitreal Conbercept injection for the treatment of choroidal neovascularization secondary to degenerative myopia: a case report.

BACKGROUND: We report a case of macular hole (MH) formation and retinal detachment after intravitreal conbercept injection for the treatment of choroidal neovascularization (CNV) secondary to degenerative myopia. CASE PRESENTATION: A 60-year-old woman presented with blurred vision in her left eye was diagnosed as CNV secondary to degenerative myopia. Intravitreal injection of conbercept, an anti -vascular endothelial growth factor (VEGF) agent, was uneventfully performed in the left eye. Unfortunately, a full thickness MH and retinal detachment was found three weeks postoperatively by ophthalmoscopy and spectral-domain optical coherence tomography. Vitrectomy, internal limiting membrane peeling and silicone oil tamponade were then performed, and macular retina was reattached soon after surgery. However, MH still kept open during three months' follow-up. CONCLUSION: MH is a quite rare complication of intravitreal anti- VEGF agent injection, tangential contraction secondary to CNV shrinkage and regression caused by anti-VEGF agent is proposed to be the major pathogenesis of MH formation.

Design, synthesis and biological evaluation of lazabemide derivatives as inhibitors of monoamine oxidase.

In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC50 = 3.12 ±â€¯0.05 µmol/mL of MAO-A and compound 3m was IC50 = 5.04 ±â€¯0.06 µmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity.

Design, synthesis and bioactivities of Celecoxib analogues or derivatives.

A series of Celecoxib analogues or derivatives were designed and synthesized, and their biological activities were studied. The results of inhibitory activity in vitro proved that compounds 1a, 1h, 1i, 1l and 1p had better inhibitory effect on COX-2, and the selectivity was higher. Among them, the inhibitory activity of compound 1h to COX-2 was IC50=0.049µmol/L and SI >1000. Moreover, the experimental results of anti-inflammatory activity in vivo showed that they had good anti-inflammatory activity and could inhibit the release of PGE-2. Therefore, these compounds have better druggability.

Design, synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis.

A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by 1H NMR, 13C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0 µg/mL.

[Characteristics and Risk Assessment of Antibiotic Contamination in Oujiang River Basin in Southern Zhejiang Province].

Antibiotic pollution in the environment has a negative impact on ecosystem security. Taking the Oujiang River Basin as an example,high-performance liquid chromatography mass spectrometry(LC-MS)was used to detect the concentration of six classes of 35 antibiotics in the surface water of the southern Zhejiang River Basin. The concentration level and spatial distribution of antibiotics were analyzed,the risk of antibiotics to ecology and human health were assessed using relevant models,and the sources of antibiotics were discussed. The results showed that in 20 sampling sites,a total of four classes of 12 antibiotics were detected,including sulfonamides,quinolones,tetracyclines,and lincosamides. The total concentration was ND-1 018 ng·L-1. The highest detection rate was that of Lincomycin(90.48%),followed by that of sulfapyridine(38.10%). The three antibiotics with the highest average concentrations were ofloxacin(12.49 ng·L-1),Lincomycin(11.08 ng·L-1),and difloxacin(7.38 ng·L-1). Antibiotics in the basin showed mainly spotty pollution,which had large spatial differentiation. The average concentration of antibiotics in the upstream(54.39 ng·L-1)was higher than that mid-downstream(46.64 ng·L-1). The degree of antibiotic pollution from upstream to downstream showed a characteristic of being "sparse in the upstream and dense in the downstream. " This indicated that the concentration of antibiotics in the upstream was significantly different,whereas the pollution degree of antibiotics in the downstream was uniform. The upstream was mainly polluted by health,livestock,and poultry breeding wastewater emissions,and downstream pollution was mainly caused by densely populated activities and the rapid development of economy,trade,and industry. The ecological risk assessment results showed that the upstream site H6 had the highest risk quotient,ofloxacin and enrofloxacin had high risk levels, and lincomycin had a moderate risk level. Health risk assessment results showed that the Oujiang River surface water antibiotics posed no risk to human health.

Some important inhibitors and mechanisms of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic disease that seriously affects human health and quality of life, and it is one of the main causes of labor loss and disability. Many countries have listed rheumatoid arthritis as one of the national a key diseases to tackle. The pathogenesis of RA in humans is still unknown, and medical researchers believe that the pathogenesis of RA may be the result of a combination of genetic and environmental factors. RA is an incurable condition that can only be controlled and treated with conventional drugs. In this paper, the pathologic features and pathogenesis of RA were introduced, and the research progress of new anti-rheumatoid arthritis chemical drugs in recent years was reviewed.

Synthesis and inhibitory activities of inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with unknown etiology and pathogenesis, in which butyrylcholinesterase (BuChE) plays an important role in the pathogenesis and progression. Inhibition of BuChE is a potential strategy for the treatment of advanced AD. Herein, the advantages and disadvantages of various synthesis methods on BuChE inhibitors and their inhibitory activities were summarized.

The biological activities of butyrylcholinesterase inhibitors.

Acetylcholinesterase (AChE) inhibitor is the first choice for the treatment of Alzheimer's disease (AD), but it has some defects, such as dose limitation and unsatisfactory long-term treatment effect. Recent studies have shown that butyrylcholinesterase (BuChE) inhibitors or double acetyl and butyryl cholinesterase inhibitors have better curative effects on AD, and the side effects are lower than those of specific AChE inhibitors. Dual target cholinesterase inhibitors have become a new hotspot in the research of anti-AD drugs. Herein, the synthesis and bioactivities of BuChE inhibitors were reviewed.

Extraction, derivatization, and antioxidant activity of Morinda citrifolia polysaccharide.

The polysaccharide from Morinda citrifolia fermentation liquor was extracted by the hot water method. The acetylated polysaccharide, phosphorylated polysaccharide, carboxymethylated polysaccharide, and sulfated polysaccharide were identified by IR and NMR spectra. The results showed that Morinda citrifolia polysaccharide and its derivatives showed the good antioxidant activity, and them up to Vc level. These results provide a good basis for studying the antioxidant activity and structural-activity relationship of Morinda citrifolia polysaccharide and its derivatives.

Extraction, derivatization and antioxidant activities of onion polysaccharide.

The preparation of purified polysaccharides was described from fresh onions by hot water extraction, protein removal and dialysis treatment. The structure of onion polysaccharide was confirmed by 13C NMR, DEPT, COSY, HSQC and HMBC. In order to study the structure-activity relationship of onion polysaccharide, the derivatives of onion polysaccharide including acetylated onion polysaccharide and phosphoric onion polysaccharide were prepared. On this basis, the antioxidant activities of onion polysaccharide and its derivatives were tested in vitro. The results showed that onion polysaccharides and its derivatives had a good antioxidant activity, and the activity of phosphorylated polysaccharide was similar to that of Vc positive control.

Synthesis and anti-tumor activity of Fissitungfine B compounds.

In order to explore the potential anti-tumor activity functional molecules, a series of Fissitungfine B derivatives were designed and synthesized. Their anti-tumor activity effects on Hela, MCF-7 and A-549 cell lines were evaluated in vitro. The results showed that some of these Fissitungfine B derivatives exhibited moderate to good anti-tumor activities. Especially, compound 4 g with the highest inhibitory activities against all tested cell lines with the Hela was IC50  = 3.82 ± 0.56 µM, MCF-7 was IC50  = 5.53 ± 0.68 µM, and A-549 was IC50  = 4.55 ± 0.53 µM. Furthermore, the compounds 4 g have higher inhibitory effects on TDP2 in vitro. In vivo, the biological activities assay results showed that the target compound 4 g had a good inhibitory effect on tumor growth. The target compound 4 g could inhibit tumor growth well, which might be use as a candidate drug or lead compound for further research and development anti-tumor agents.

Design and Synthesis of Novel Double-Ring Conjugated Enones as Potent Anti-rheumatoid Arthritis Agents.

Rheumatoid arthritis (RA) is a chronic and systemic disease of inflammatory synovitis with unknown etiology. In previous studies, we found that the double-ring conjugated enone structure has anti-rheumatoid arthritis activity and could effectively inhibit the proliferation of rat synovial cells in vitro and has good anti-inflammatory activity in vivo. Herein, we further modified the structure, which was a novel double-ring conjugated enone, to study its anti-rheumatoid arthritis activity. Results showed that the most potent compound 32 could effectively inhibit the proliferation of rat synovial cells in vitro and has better anti-inflammatory activity compared with that of the positive control methotrexate, as shown by in vivo activity evaluation. More interestingly, compound 32 could effectively inhibit the increase of TNF-α, IL-1ß, and IL-6 induced by LPS and regulate the expression of TLR4, MyD88, NF-κB, and IκB in the signaling pathway of TLR4/NF-κB. Our results provided a promising starting point for the development of highly effective small molecules for the treatment of RA.