New azole derivatives linked to indole/indoline moieties combined with FLC against drug-resistant Candida albicans.

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.

Exploration of costunolide derivatives as potential anti-inflammatory agents for topical treatment of atopic dermatitis by inhibiting MAPK/NF-κB pathways.

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.

Synthesis and Antifungal Evaluation of New Azole Derivatives against Candida albicans.

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.

Optimization and antifungal activity of quinoline derivatives linked to chalcone moiety combined with FLC against Candida albicans.

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.

Anticancer evaluation of benzofuran derivatives linked to dipiperazine moiety.

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.

Synthesis and Cytotoxic Activity of Quinazoline-Benzofuran Conjugates.

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.

Antifungal evaluation of quinoline-chalcone derivatives combined with FLC against drug-resistant Candida albicans.

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.

MW­9, a chalcones derivative bearing heterocyclic moieties, attenuates experimental autoimmune encephalomyelitis via suppressing pathogenic TH17 cells.

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 IFN­Î³) 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.

Discovery of novel indole and indoline derivatives against Candida albicans as potent antifungal agents.

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.

Copper(II)-catalyzed Synthesis of Benzoxazoles from Inactive 2-chloroanilides.

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.

Synthesis and antifungal evaluation of phenol-derived bis(indolyl)methanes combined with FLC against Candida albicans.

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.

Discovery of heterocyclic substituted dihydropyrazoles as potent anticancer agents.

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.

Flower extract of Caragana sinica. ameliorates DSS-induced ulcerative colitis by affecting TLR4/NF-κB and TLR4/MAPK signaling pathway in a mouse model.

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.

Cu(II)/Vasicine Promoted Intramolecular C-O Formation: Synthesis of Benzoxazoles in EtOH.

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.

Synthesis of New Piperazine Substituted Chalcone Sulphonamides as Antibacterial Agents.

BACKGROUND: Infection is a global threat to human health, and there is an urgent need to develop new effective antibacterial drugs to treat bacterial infections. OBJECTIVE: To study the antibacterial activity of piperazine substituted chalcone sulphonamides. MATERIALS AND METHODS: A series of novel piperazine substituted chalcone sulphonamides have been prepared, and in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis and Escherichia coli strains were evaluated. RESULTS: The results showed that derivatives 6a, 6c and 6h displayed good antibacterial activity against Bacillus subtilis with MIC values of 4.0-8.0 mg/mL. CONCLUSION: Piperazine substituted chalcone sulphonamides may be used as potential antibacterial agents.

Synthesis and anti-inflammatory evaluation of new chalcone derivatives bearing bispiperazine linker as IL-1ß inhibitors.

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.

Synthesis and Biological Evaluation of Heterocyclic Substituted Bis(indolyl)methanes.

BACKGROUND: Bis(indolyl)methane derivatives are widely found in nature with a broad range of biological and pharmacological activities. The development of techniques for the synthesis and functionalization of bis(indolyl)methanes have attracted more and more attention in recent years. OBJECTIVE: To study the synthesis and biological activity of heterocyclic substituted bis(indolyl)methanes. MATERIALS AND METHODS: A series of heterocyclic substituted bis(indolyl)methanes (3a-3p) have been prepared by condensation reaction of indole and heterocyclic aldehydes catalyzed by boron trifluoride etherate with high yields. Preliminary in vitro anti-inflammatory in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and cytotoxic activity against human tumor cell lines (A549, Hela and SGC7901) by MTT assay were tested. RESULTS: The result indicated that heterocyclic substituted bis(indolyl)methanes showed good antiinflammatory and selective cytotoxic activity. Especially, compounds 3o, 3p and 3q displayed similar inhibitory effect on the generation of NO to positive control dexamethasone, and compound 3q displayed similar selective cytotoxic activity to 5-FU. CONCLUSION: Heterocyclic substituted bis(indolyl)methanes may be used as potential anti-inflammatory and anticancer leads.

Efficient Cu-catalyzed intramolecular O-arylation for synthesis of benzoxazoles in water.

An efficient method was developed for synthesis of benzoxazoles by Cu-catalyzed intramolecular O-arylation of o-halobenzanilides in water. This strategy provides several advantages, such as high yields, water as a green solvent and functional groups tolerance.

2-Benzoylbenzofuran derivatives possessing piperazine linker as anticancer agents.

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.

Novel Resveratrol-chalcone Derivatives: Synthesis and Biological Evaluation.

INTRODUCTION: Resveratrol and chalcones are lead compounds with good biological activities. METHOD: In this study, a series of novel derivatives (6-38) between resveratrol and chalcone possessing piperazine moiety have been synthesized, and in vitro anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and anti-proliferative effect on a panel of human tumor cell lines (Hela, A549 and SGC7901) by MTT assay were evaluated. RESULT: The results demonstrated that the substituents of the NH group of piperazine ring had an obvious influence on biological activities. Especially, compounds 13, 17, 30, 31 and 36 showed good inhibitory effect on the generation of NO compared to dexamethasone. Furthermore, analogs 20, 21, 22 and 25 were found to be the better anti-proliferative effect on 3 human tumor cell lines, which were found to be a better cytotoxic activity to positive control 5-FU. Many compounds displayed low cytotoxic effect on normal cells L02. CONCLUSION: Further FACs analysis showed that compounds 20 and 25 significantly induced apoptosis in A549 cell. These derivatives were considered as the potential anti-inflammatory and anti-tumor agents.