ABSTRACT
Psoriasis is a chronic inflammatory disease and is difficult to cure. In this work, a series of novel chrysin derivatives have been designed and prepared while evaluating anti-inflammatory activities in vitro and in vivo. In vitro, RAW264.7 cells were used to detect the inflammatory activities at first, and compounds 4h, 4k, and 4o significantly decreased the levels of NO, TNF-α, and IL-6. In particular, compound 4o showed superior anti-inflammatory activities than other compounds. Moreover, compound 4o decreased the level of IL-17A in LPS-induced HaCaT cells in vitro. The effect and mechanism of anti-inflammatory activities on psoriasis were determined by imiquimod (IMQ)-induced psoriasis-like mice in vivo. Compound 4o deduced the level of IL-6, IL-17A, IL-22, IL-23, and TNF-α, and showed potent anti-psoriasis activity. Further mechanism study suggested that compound 4o could improve the skin inflammation of psoriasis by inhibiting the NF-κB and STAT3 signaling pathways.
Subject(s)
Flavonoids , Psoriasis , Psoriasis/drug therapy , Psoriasis/chemically induced , Flavonoids/pharmacology , Flavonoids/chemistry , Flavonoids/chemical synthesis , Animals , Mice , Humans , Structure-Activity Relationship , Molecular Structure , RAW 264.7 Cells , Dose-Response Relationship, Drug , Drug Discovery , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/therapeutic use , Imiquimod , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Mice, Inbred BALB CABSTRACT
Atopic dermatitis (AD) is a common inflammatory disease and it is very difficult to treat. In the present work, a series of costunolide derivatives have been prepared, and in vitro and in vivo anti-inflammatory activities have evaluated. The results showed that most derivatives displayed good inhibition of NO generation with low cytotoxicity, and 7d could inhibit the phosphorylation of P38, P65 NF-κB and IκB-α in LPS-induced RAW264.7 model. The in vivo researches showed that 7d could improve skin injury symptoms, decrease Th2-type cytokine levels, inhibit HIS levels, alleviate scratching and repaire the damaged skin barrier through the inhibition of phosphorylation of MAPK and NF-κB signaling pathways on MC903-induced AD model. Therefore, costunolide derivatives may be new potent anti-AD agents for further study.
Subject(s)
Dermatitis, Atopic , Sesquiterpenes , Anti-Inflammatory Agents/adverse effects , Cytokines/metabolism , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Lipopolysaccharides/adverse effects , NF-kappa B/metabolism , Tumor Necrosis Factor-alpha/metabolism , RAW 264.7 Cells , Mice , AnimalsABSTRACT
In this work, a series of novel benzofuran derivatives linked to dipiperazine moiety have been prepared, and in vitro anticancer activity against Hela and A549 was investigated. The results demonstrated that benzofuran derivatives exerted potent antitumor effect. Especially, compounds 8c and 8d showed better antitumor activity against A549 (IC50 = 0.12 µM and 0.43 µM). Further mechanism study indicated that compound 8d could significantly induce cell apoptosis in A549 by FACs analysis.
Subject(s)
Antineoplastic Agents , Benzofurans , Humans , Antineoplastic Agents/pharmacology , Cell Proliferation , HeLa Cells , Benzofurans/pharmacology , Drug Screening Assays, Antitumor , Structure-Activity Relationship , Molecular Structure , Cell Line, Tumor , ApoptosisABSTRACT
With the widespread clinical use of FLC, the FLC-resistant C. albicans greatly increases the difficulty of treatment, and drug combination becomes an important method to treat C. albicans infection. In this work, we have prepared a series of quinoline-chalcone derivatives in good yields, and in vitro antifungal activity against C. albicans were evaluated. The results indicated that most title compounds combined with FLC showed good antifungal activity against drug-resistant C. albicans. Further mechanism researches demonstrated that 6a and 6c combined with FLC could significantly inhibited growth and biofilm formation of C. albicans, induce ROS accumulation, impair the mitochondrial membrane, and decrease intracellular ATP concentrations.
Subject(s)
Antifungal Agents , Chalcones , Antifungal Agents/pharmacology , Candida albicans , Fluconazole/pharmacology , Chalcones/pharmacology , Drug Synergism , Microbial Sensitivity Tests , Drug Resistance, FungalABSTRACT
With the widespread use of azole antifungals in the clinic, the drug resistance has been emerging continuously. In this work, we have designed and prepared a series of novel indole and indoline derivatives, and in vitro antifungal activity against C. albicans were evaluated. The results showed that title compounds exhibited good antifungal effect on Azole-resistant C. albicans. Further mechanism study demonstrated that S18 could inhibit the biofilm formation and hyphae growth of C. albicans through the Ras-cAMP-PKA signaling pathway.
Subject(s)
Antifungal Agents , Candida albicans , Antifungal Agents/pharmacology , Azoles/pharmacology , Biofilms , Indoles/pharmacology , Microbial Sensitivity TestsABSTRACT
With the widespread use of azole antifungals in the clinic, the drug resistance has been emerging continuously. In this work, we focus on boron trifluoride etherate catalyzed condensation of indole and salicylaldehydes to form bis(indolyl)methanes (BIMs) in high yields, and in vitro antifungal activity against Candida albicans were evaluated. The results showed that most phenol-derived BIMs combined with fluconazole (FLC) exhibited good antifungal activity against sensitive and drug-resistant C. albicans. Further mechanism study demonstrated that BI-10 combined with FLC could inhibit hyphal growth, result in ROS accumulation, and decrease mitochondrial membrane potential (MMP) as well as altering membrane permeability.
Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Fluconazole/pharmacology , Indoles/pharmacology , Methane/pharmacology , Phenols/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Dose-Response Relationship, Drug , Drug Resistance, Fungal/drug effects , Fluconazole/chemistry , Indoles/chemistry , Methane/chemistry , Microbial Sensitivity Tests , Molecular Structure , Phenols/chemistry , Structure-Activity RelationshipABSTRACT
In this work, a series of novel heterocyclic substituted dihydropyrazole derivatives have been prepared, and in vitro anticancer activity against a panel of human tumor cell lines by SRB were evaluated. The results indicated that piperazine substituted dihydropyrazole derivatives exhibited superior anticancer activity than that of other compounds. Especially, compounds 4g, 4h, 4l, 4m, 4o, 6g, 6j and 6l showed potent antitumor activity. Further mechanism study demonstrated that compound 4o could induce G2/M arrest in HCC1806 cell and p21 accumulation significantly.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Pyrazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
In this work, a series of novel chalcone derivatives bearing bispiperazine linker have been synthesized and in vitro anti-inflammatory, cytotoxic activity and anti-inflammatory mechanism have been screened. The results indicated that most bispiperazinochalcone derivatives displayed good inhibition of NO (IC50 < 20 µM) and low cytotoxicity (CC50 > 40 µM), and selectively inhibited the production of IL-1ß via inhibiting NLRP3 inflammasome activation, as promising candidate compounds for the treatment of NLRP3 inflammasome-driven diseases.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chalcone/pharmacology , Interleukin-1beta/antagonists & inhibitors , Piperazine/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Chalcone/chemical synthesis , Chalcone/chemistry , Dose-Response Relationship, Drug , Interleukin-1beta/biosynthesis , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred DBA , Molecular Structure , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Piperazine/chemistry , RAW 264.7 Cells , Structure-Activity RelationshipABSTRACT
A series of novel 2-benzoylbenzofuran derivatives possessing piperazine linker have been prepared, and their in vitro anticancer activity against a panel of human tumor cell lines by MTT assay were evaluated. The results demonstrated that tertiary amine derivatives exhibited better cytotoxic activity, and SAR study revealed that electron-donating substituents on the phenyl ring of the derivatization functionality contributed to potent anticancer activities. Among them, compounds 6, 9, 11, 18, 23 and 25 displayed both better anti-tumor activity and lower cytotoxic effect on human normal liver cell L02. Further apoptosis analysis showed that compound 18 significantly induced apoptosis in A549 cell, which was considered as the most potent anticancer agent.
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Piperazines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Benzofurans/chemical synthesis , Benzofurans/toxicity , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Piperazines/chemical synthesis , Piperazines/toxicity , Structure-Activity RelationshipABSTRACT
A series of novel hybrid compounds between benzofuran and N-aryl piperazine have been designed and prepared. These derivatives were evaluated for their in vitro anti-tumor activity against a panel of human tumor cell lines by MTT assay. The results demonstrated that amide derivatives were more bioactive than sulfonamide compounds in general, and that chloro or trifluoromethyl substituent was vital for modulating cytotoxic activity. In particular, compound 13 was found to be the most potent compound against 4 strains human tumor cell lines, and exhibited cytotoxic activity selectively against Hela (0.03µM).
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Drug Design , Piperazines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzofurans/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Piperazine , Piperazines/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel hybrid compounds between benzofuran and N-aryl piperazine have been synthesized and screened in vitro for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and for anticancer activity against three human tumor cell lines. The results demonstrated that derivative 16 not only had inhibitory effect on the generation of NO (IC50 = 5.28 µM), but also showed satisfactory and selective cytotoxic activity against human lung cancer line (A549) and gastric cancer cell (SGC7901) (IC50 = 0.12 µM and 2.75 µM, respectively), which was identified as the most potent anti-inflammatory and anti-tumor agent in this study.
Subject(s)
Antineoplastic Agents , Benzofurans , Lung Neoplasms/drug therapy , Piperazines , Stomach Neoplasms/drug therapy , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Nitric Oxide/biosynthesis , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/pharmacology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathologyABSTRACT
Candida albicans is the most common fungal pathogen associated with human opportunistic infections. Invasive infections caused by C. albicans are becoming increasingly serious. However, with the rising incidence of fungal infection, many fungi are resistant to commonly used drugs. Therefore, there is an urgent need for exploring new anti-fungal drugs that fungi are not resistant to. A series of novel azole derivatives linked to indole/indoline moieties were prepared, and in vitro antifungal activity evaluated. All compounds combined with FLC showed excellent activity against drug-resistant C. albicans with low toxicity. A preliminary mechanistic study indicated that S1 combined with FLC could inhibit the formation of C. albicans biofilms as well as destroy the integrity of cell-membrane structure and mitochondrial function. S1 could be considered a new fungal agent for further study.
ABSTRACT
Previous studies have indicated that heterocyclic substituted dihydropyrazole derivatives, particularly MW-19, potentially exert anticancer activity in vitro; however, the underlying mechanism remains unknown. The present study was designed to investigate the mechanisms underlying MW-19 activity in triple-negative breast cancer cells. A sulforhodamine B assay was performed to evaluate cell proliferation inhibition rates, and the antitumor effect of MW-19 was evaluated in mice with HCC-1806 xenografts. Apoptosis was analyzed by Hoechst 33342 and annexin V/propidium iodide staining. Expression of pro- and antiapoptotic proteins and mRNA were analyzed by western blotting and reverse transcription-quantitative (RT-q) PCR, respectively. We found that MW-19 significantly inhibited HCC-1806 cell proliferation in a dose- and time-dependent manner, and significantly inhibited MDA-MB-231 cell migration. Importantly, oral administration of MW-19 significantly inhibited HCC-1806 tumor growth in BALB/c-nu/nu mice. Moreover, MW-19 treatment induced marked apoptosis and G2/M arrest in the sensitive cell line, HCC-1806. RT-qPCR analysis showed that levels of proapoptotic genes (Bax, caspase-3, caspase-7, and Fas) were considerably increased in the MW-19 group relative to the control group, while those of antiapoptotic factors (Bcl-2, C-MYC) were dramatically decreased. Consistently, Bax, caspase-3, and caspase-7 were significantly induced after MW-19 treatment, while levels of phosphorylated (p-)AKT, p-PI3K, p-ERK, and the antiapoptotic protein, Bcl-2, were clearly diminished, and the P38 MAPK signaling pathway was activated. Furthermore, P38 pharmacological inhibitors abrogated MW-19-induced apoptosis. Together, our findings indicate that MW-19 exerts antitumor effects by targeting PI3K/AKT and ERK/P38 signaling pathways.
Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Mice, Inbred BALB C , Pyrazoles , Triple Negative Breast Neoplasms , Apoptosis/drug effects , Humans , Animals , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Female , Cell Line, Tumor , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/chemical synthesis , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Mice, Nude , Cell Movement/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Xenograft Model Antitumor Assays , Phosphatidylinositol 3-Kinases/metabolismABSTRACT
AIMS: In order to study on structure-activity relationships of benzofurans. BACKGROUND: Benzofuran is a kind of natural compound widely existing in nature with pharmacological effects. The development of new anticancer benzofuran derivatives has attracted more and more attention. METHOD: We have introduced an active quinazoline unit into piperazine-substituted benzofuran, prepared a series of quinazoline-benzofuran compounds, and evaluated cytotoxic activity against a panel of human tumor cell lines by MTT assay. RESULT: 48 novel quinazoline-substituted benzofuran derivatives have been prepared, and in vitro, cytotoxic activity against five human tumor cell lines was evaluated. The results indicated that some quinazoline-benzofuran conjugates showed selective inhibitory activity against tumor cell lines. CONCLUSION: We have found that compound 14x displayed excellent cytotoxic activity, which could be considered a potential anticancer agent.
ABSTRACT
In this study, we designed and prepared a series of new azole derivatives by recombination of fluconazole (FLC) and ketoconazole units, and in vitro antifungal activities against Candida albicans were evaluated. The results indicated that most azoles showed good antifungal activity against the drug-sensitive C. albicans strain, especially compounds 6a, 6e, 6n, 6p, 6r, 6s, 6t, and 6v, which displayed better antifungal activity (MIC50 < 1.0 µg/mL) than FLC against SC5314. The further mechanism study showed that compound 6r could significantly inhibit the formation of C. albicans biofilm, increase the permeability of the cell membrane, reduce the ergosterol level of the cell membrane, damage the membrane structure, and destroy the integrity of the cell structure to exert excellent antifungal activity. Subsequently, a molecular docking study indicated that azole compounds could inhibit cytochrome P450 14α-demethylase (CYP51). Therefore, these azole derivatives can be considered as potent antifungal drugs to treat fungal infections.
ABSTRACT
In present work, a series of quinoline derivatives linked to chalcone moiety have been prepared, and their in vitro and in vivo antifungal activities against C. albicans have been evaluated. The results indicated that quinoline combined with fluconazole (FLC) showed good inhibitory activity against C. albicans. Especially, compound PK-10 combined with FLC displayed the best antifungal activity against 14 FLC-resistant C. albicans strains with almost no cytotoxicity. Preliminary mechanistic studies proved that PK-10 combined with FLC could inhibit the hyphae formation of C. albicans, induce the accumulation of reactive oxygen species (ROS), the damage of mitochondrial membrane potential and the decrease of intracellular ATP content, which led to mitochondrial dysfunction. In vivo studies found obvious effects of the co-treatment regimen had obvious effects based on histological analysis, body weight curves, and coefficients of major organs. Therefore, the optimization of quinolone-chalcone derivatives combined with FLC could exert the potent antifungal activity in vitro and in vivo obviously, suggesting them as new agents to treat drug-resistant C. albicans infection.
Subject(s)
Antifungal Agents , Chalcones , Hydroxyquinolines , Quinolones , Antifungal Agents/pharmacology , Candida albicans/drug effects , Chalcones/pharmacology , Fluconazole/pharmacology , Hydroxyquinolines/pharmacology , Quinolones/pharmacologyABSTRACT
AIM AND OBJECTIVE: Benzoxazoles are of great importance in natural products, pharmaceutical agents as well as synthetic intermediates. Although many works on the construction of benzoxazoles by Cu-catalyzed intramolecular O-arylation of ortho-haloanilides have been reported, only a few reports about transition metal-catalyzed synthesis of benzoxazoles from inactive 2-chloroanilides so far. This work aimed to explore a green and cheap protocol for intramolecular O-arylation of inactive 2-chloroanilides to prepare 2-arylbenzoxazoles. MATERIALS AND METHODS: We found that Cu(acac)2/1,10-Phen complex was beneficial to intramolecular O-arylation of 2-chloroanilides using K2CO3 as a base in EtOH at 90 °C to prepare benzoxazoles. RESULTS: An efficient and green method was developed for Cu(II)-catalyzed intramolecular Oarylation of inactive 2-chloroanilides. CONCLUSION: In this way, many 2-arylbenzoxazoles were prepared in good yields.
Subject(s)
Benzoxazoles , Copper , Catalysis , CyclizationABSTRACT
Previous studies have indicated that MW9, a chalcones derivative bearing heterocyclic moieties, has considerable antiinflammatory activity in vitro. Whether MW9 may be used to treat inflammationbased diseases, such as multiple sclerosis, remains unknown. The present study was designed to determine the effect and underlying mechanism of MW9 in experimental autoimmune encephalomyelitis (EAE). Female C57BL/6 mice immunized with MOG3555 were treated with or without MW9, then the clinical scores and other relevant parameters were investigated. Production of cytokines and specific antibodies were monitored by ELISA assays. Surface marker, Treg cell, and intracellular cytokines (IL17A and IFNγ) were detected by flow cytometry, and mRNA expression in the helperT (TH)17 cellrelated signaling pathway was examined by reverse transcriptionquantitative (RTq) PCR analysis. TH17 cell differentiation assay was performed. Herein, the present results demonstrated that oral administration of MW9 reduced the severity of disease in EAE mice through slowing down infiltration process, inhibiting the demyelination, blocking antiMOG3555 IgG antibody production (IgG, IgG2a and IgG3), and decreasing accumulation of CD11b+Gr1+ neutrophils from EAE mice. MW9 treatments also led to significantly decreased IL17A production and IL17 expression in CD4+ Tcells, but had no detectable influence on development of TH1 and Tregulatory cells ex vivo. RTqPCR analysis showed that within the spinal cords of the mice, MW9 blocked transcriptional expression of TH17associated genes, including Il17a, Il17f, Il6 and Ccr6. In TH17 cell differentiation assay, MW9 inhibited differentiation of 'naïve' CD4+ Tcells into TH17 cells and reduced the IL17A production. The data demonstrated that MW9 could attenuate EAE in part through suppressing the formation and activities of pathogenic TH17 cells.
Subject(s)
Chalcones , Encephalomyelitis, Autoimmune, Experimental , Animals , Cell Differentiation , Chalcones/pharmacology , Cytokines/metabolism , Female , Immunoglobulin G/pharmacology , Interleukin-17/pharmacology , Mice , Mice, Inbred C57BL , Th1 Cells , Th17 CellsABSTRACT
AIMS AND OBJECTIVES: Benzoxazoles are valuable bicyclic aromatic compounds; the construction of benzoxazoles via C-O cross-coupling reactions has attracted more and more attention. MATERIALS AND METHODS: The best condition of C-O bond formation from o-haloanilides was carried out, taking Cu(OTf)2 (5 mol%) and vasicine (10 mol%) as the catalysts in EtOH in the presence of K2CO3 (2 eq.) for 12 h at 90°C. RESULTS: A series of 2-substituted benzoxazoles have been prepared in high yields from 2-bromoanilides and 2- iodioanilides under mild conditions. CONCLUSION: We have developed an efficient Cu-vasicine catalytic system for intramolecular C-O bond formation. This strategy is applicable to the synthesis of a wide variety of 2-substituted benzoxazoles by intramolecular O-arylation of o-haloanilides.
ABSTRACT
OBJECTIVES: This study aimed to find out the protective effects and preliminary mechanisms of the flower extract of Caragana sinica (FEC) on dextran sulfate sodium salt (DSS)-induced colitis. MATERIALS AND METHODS: The ulcerative colitis models of mice induced by 3% DSS were established and treated with FEC. Body weight changes, disease activity index (DAI), colon histopathological score, anti-oxidant ability, and the level of inflammatory cytokines were determined. The expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) were assessed in colonic tissue by immunohistochemical staining. Western blot was used to analyze the expression of TLR4/ nuclear factor kappa-B (NF-κB) and TLR4/ mitogen-activated protein kinase (MAPK) signaling pathway-related proteins. RESULTS: FEC significantly prevented body weight loss and colonic shortening and reduced the disease activity index and histopathological score (P<0.05). Moreover, FEC treatment remarkably down-regulated the levels of myeloperoxidase (MPO), interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) and up-regulated the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and interleukin 10 (IL-10) in the colon of DSS mice (P<0.05). Furthermore, the expression of TLR4/NF-κB and TLR4/MAPK pathway-related proteins was inhibited by FEC (P<0.05). CONCLUSION: Our findings demonstrated that FEC could serve as a potential therapeutic agent for treatment of ulcerative colitis.