A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.
- MeSH
- Ampicillin pharmacology MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Methicillin-Resistant Staphylococcus aureus * MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis * MeSH
- Swine MeSH
- Mammals MeSH
- Staphylococcal Infections * MeSH
- Staphylococcus aureus MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
Extensive phytochemical analysis of the CHCl3-soluble part of an ethanolic extract of branches and twigs of Broussonetia papyrifera led to the isolation of fourteen compounds, including a novel 5,11-dioxabenzo[b]fluoren-10-one derivative named broussofluorenone C (12). The isolated compounds 1-14 were characterized based on their NMR and HRMS data, and examined for their anti-inflammatory activities in LPS-stimulated THP-1 cells as well as for their cellular antioxidant effects. Compounds 7-10 and 12 showed inhibitory effects on NF-κB/AP-1 activation and compounds 7-9 were subsequently confirmed to suppress the secretion of both IL-1β and TNF-α in LPS-stimulated THP-1 cells more significantly than the prednisone used as a positive control. In the CAA assay, compound 10 exhibited the greatest antioxidant effect, greater than that of the quercetin used as a positive control. The results show possible beneficial effects and utilization of B. papyrifera wood in the treatment of inflammatory diseases as well as oxidative stress.
- MeSH
- Anti-Inflammatory Agents chemistry isolation & purification pharmacology MeSH
- Antioxidants chemistry isolation & purification pharmacology MeSH
- Broussonetia chemistry MeSH
- Interleukin-1beta antagonists & inhibitors biosynthesis MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Lipopolysaccharides antagonists & inhibitors pharmacology MeSH
- Molecular Structure MeSH
- NF-kappa B analysis antagonists & inhibitors biosynthesis MeSH
- Oxidative Stress drug effects MeSH
- THP-1 Cells MeSH
- Tumor Necrosis Factor-alpha antagonists & inhibitors biosynthesis MeSH
- Transcription Factor AP-1 analysis antagonists & inhibitors biosynthesis MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
ETHNOPHARMACOLOGICAL RELEVANCE: Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. AIM OF THE STUDY: This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. MATERIALS AND METHODS: LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1β and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. RESULTS: MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1β and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. CONCLUSION: Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.
- MeSH
- Anti-Inflammatory Agents isolation & purification pharmacology therapeutic use MeSH
- Cytoprotection drug effects physiology MeSH
- Euphorbiaceae * MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Lipopolysaccharides toxicity MeSH
- Inflammation Mediators antagonists & inhibitors metabolism MeSH
- Microglia drug effects metabolism MeSH
- Monocytes drug effects metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Prenylation drug effects physiology MeSH
- Plant Extracts isolation & purification pharmacology therapeutic use MeSH
- Stilbenes isolation & purification pharmacology therapeutic use MeSH
- Dose-Response Relationship, Drug MeSH
- Inflammation drug therapy metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.
- MeSH
- Antioxidant Response Elements drug effects MeSH
- Antioxidants chemistry pharmacology MeSH
- Hep G2 Cells MeSH
- NF-E2-Related Factor 2 genetics MeSH
- Humans MeSH
- Lipid Peroxidation drug effects MeSH
- Pyocyanine chemistry MeSH
- Stilbenes chemistry pharmacology MeSH
- Thiobarbiturates chemistry MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) was further evaluated using LPS-stimulated THP-1 macrophages.
- MeSH
- Cell Line MeSH
- Prostaglandin-Endoperoxide Synthases metabolism MeSH
- Enzyme Inhibitors pharmacology MeSH
- Humans MeSH
- Lipoxygenases metabolism MeSH
- NF-kappa B antagonists & inhibitors MeSH
- Prenylation * MeSH
- Signal Transduction drug effects MeSH
- Stilbenes pharmacology MeSH
- Transcription Factor AP-1 antagonists & inhibitors MeSH
- Inflammation prevention & control MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC50: 0.96 μg/mL; selectivity index CC50/IC50: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC50: 1.92 μg/mL; selectivity index CC50/IC50: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC50: 0.73 μg/mL; selectivity index CC50/EC50: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC50: 1.75 μg/mL; selectivity index CC50/EC50: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α.
- MeSH
- Anti-Bacterial Agents chemistry pharmacology MeSH
- Anti-Inflammatory Agents chemistry pharmacology MeSH
- Anti-Infective Agents chemistry pharmacology MeSH
- Antioxidants metabolism MeSH
- Antiviral Agents chemistry pharmacology MeSH
- Cell Line MeSH
- Chlorocebus aethiops MeSH
- Cytokines metabolism MeSH
- Eucalyptus chemistry MeSH
- Herpes Simplex metabolism virology MeSH
- Humans MeSH
- NF-kappa B metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Plant Extracts chemistry pharmacology MeSH
- Simplexvirus drug effects physiology MeSH
- Transcription Factor AP-1 metabolism MeSH
- Vero Cells MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
