Two new azaphilones from the marine-derived fungus Penicillium sclerotiorum E23Y-1A

Two new azaphilones, penicilazaphilones F (1) and G (2) together with two known analogs (3 and 4), were isolated from fermentation cultures of the marine-derived fungus Penicillium sclerotiorum E23Y-1A. Their structures were elucidated based on spectroscopic methods, including IR, MS, 1D and 2D NMR, as well as by comparison with published data. The absolute configuration of compound 1 was unambiguously determined using electronic circular dichroism (ECD) calculation. All isolated compounds were evaluated for their anti-inflammatory effects. Compounds 1-4 inhibited the lipopolysaccharide-induced production of nitric oxide (NO) in BV-2 cells, with IC₅₀ values of 31.7 ± 1.5, 34.5 ± 1.4, 25.3 ± 2.2, and 34.8 ± 1.9 μM, respectively. In contrast, these compounds showed no obvious cytotoxicity at a concentration of 50.0 μM.     

Chemical constituents from Vietnamese mangrove Calophyllum inophyllum and their anti-inflammatory effects

In a search for anti-inflammatory activity in resources from Vietnamese mangroves, we found that a methanolic extract from the leaves of Calophyllum inophyllum (CIL) showed significant anti-inflammatory effects in vitro. Using various chromatographic techniques, we subsequently isolated 12 compounds (1–12) from a methanolic extract of CIL, including two novel compounds (1–2). The inhibitory effects of these compounds on lipopolysaccharide-induced nitric oxide (NO) production in RAW264.7 cells were also evaluated. Compound 1 significantly suppressed NO production (IC₅₀ = 2.44 ± 0.88 µM), the secretion of pro-inflammatory cytokines (including interleukin-1 beta and tumor necrosis factor alpha), and the expression of inducible nitric oxide synthase through downregulation of nuclear factor-kappa-B signaling cascades. These results suggest that C. inophyllum leaves might be a useful resource for the development of drugs for the treatment of inflammation.     

Synthesis,evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory,ulcerogenic and TNF-α inhibitory properties

A series of nine new N-substituted-4-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzamides (6a-i) derivatives was synthesized. All the compounds were screened in-vitro for BSA anti-denaturation property, antioxidant assay and p38α MAP kinase inhibition. The in vitro anti-inflammatory assay results revealed that the compounds (6f-i) showed better activity than the compounds 6a-e. Compound 6f bearing the 4-chlorophenyl group showed in vitro anti-inflammatory activity (82.35 ± 4.04) comparable to standard drug diclofenac sodium (84.13 ± 1.63) and better p38α MAP kinase inhibitory activity (IC₅₀ = 0.032 ± 1.63 µM) than the prototypic inhibitor SB203580 (IC₅₀ = 0.041 ± 1.75 µM). The selected active compounds (6f-i) were further studied in animal models for anti-inflammatory activity, ulcerogenic liability, lipid peroxidation and TNF-α inhibition potential. Compound 6f showed promising anti-inflammatory potential with a percentage inhibition of 83.73% when compared to the standard, diclofenac sodium (78.05%). Compound 6f was also found to show reduced ulcerogenic liability and lipid peroxidation in comparison to the standard. This compound also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α production in mice model (ID₅₀ = 8.23 mg/kg) in comparison to SB 203580 (ID₅₀ = 26.38 mg/kg). The molecular docking of compounds 6a-i against p38α MAP kinase receptor was also performed to understand ligand receptor interaction. Amongst all synthesized molecules compound 6f displayed highest docking score of −9.824. It showed hydrogen bonding interactions with Asn115 and pi-cation interaction with Lys53.     

Anti-inflammatory effects of two new stilbene-phenylpropanoid derivatives from Chamaecrista pumila

Two new stilbeno-phenylpropanoid compounds, given the trivial names chamaecristanols A and B (1 and 2), were isolated from the ethyl acetate-soluble partitions of separate methanol extracts of the aerial parts of Chamaecrista pumila (Lam.) K. Larsen. The structures of these compounds were determined on the basis of interpretation of their spectroscopic data and comparison with reported literature data. Their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells were evaluated. Results showed that compounds 1 and 2 significantly inhibited NO production with IC₅₀ values of 41.69 ± 1.34 and 32.14 ± 0.15 µM, respectively.     

Anti-inflammatory and antiproliferative prenylated carbazole alkaloids from Clausena vestita

Twelve prenylated carbazole alkaloids, containing a novel prenylated carbazole alkaloid, named as clausevestine (1), and 11 known prenylated carbazole alkaloids (2–12), were isolated and identified from the stems and leaves of Clausena vestita, which is a Chinese endemic plant. The chemical structure of 1 was established by means of comprehensive spectroscopic data analyses and the known compounds were determined via comparing their NMR and MS data as well as optical rotation values with those reported in literature. Especially, clausevestine (1) is an unusual prenylated carbazole alkaloid possessing an unprecedented carbon skeleton holding 20 carbon atoms. The anti-inflammatory effects and antiproliferative activities of those isolated prenylated carbazole alkaloids were tested. Prenylated carbazole alkaloids 1–12 displayed remarkable inhibitory effects on NO (nitric oxide) production with IC₅₀ values equivalent to that of the positive control (hydrocortisone). Meanwhile, prenylated carbazole alkaloids 1–12 exhibited remarkable antiproliferative activities against diverse human cancer cell lines in vitro holding the IC₅₀ values ranging from 0.32 ± 0.04 to 18.76 ± 0.18 µM. These findings indicate that these prenylated carbazole alkaloids possessing remarkable anti-inflammatory effects and antiproliferative activities could be meaningful to the discovery of new anti-inflammatory and anti-tumor candidate drugs.     

Novel phenolic and diterpenoid compounds isolated from the fruit spikes of Prunella vulgaris L. and their anti-inflammatory activities

Two novel phenolic compounds, prunellanate A (1) and prunellanate B (2), together with a diterpenoid compound, prunelladiterpenol A (3), were successfully isolated from the fruit spikes of Prunella vulgaris L. (Figure 1). Their structures were determined after extensive spectroscopic analyses including IR NMR, HR-ESI-MS empirical electronic circular dichroism (ECD), and X-ray diffraction. The biological activities of these new compounds on NO production in LPS (Lipopolysaccharide)-simulated RAW264.7 cells were evaluated. Compounds 1 and 3 showed significant anti-inflammatory activities revealing IC₅₀ values of 6.77 and 8.61 μM, respectively (aminoguanidine as positive control, IC₅₀ 20.33 ± 1.08 μM).     

Analysis of chemical constituents from Polygonatum cyrtonema after “Nine-Steam-Nine-Bask” processing

Seven new compounds, known as polygonatine N₁‒N₇ (1‒7), and a known compound (8) were isolated from the ‘Nine-Steam-Nine-Bask’ processing product of Polygonatum cyrtonema Hua. The compounds’ structures were determined by spectroscopic analysis. All compounds were tested for dipeptidyl peptidase-4 (DPP-4) inhibition, glucose transport, and anti-inflammatory activities. Compound 8 suppressed NO production with an IC₅₀ of 35.4 μM.     

Anti-inflammatory abietane diterpenoids from the seeds of Podocarpus nagi

In searching for naturally occurring anti-inflammatory agents, three new abietane-type diterpenoids, named 16-hydroxylambertic acid (1), 7-oxo-18-hydroxyferruginol (2), and 5α,12-dihydroxy-6-oxa-abieta-8,11,13-trien-7-one (3), were isolated from the seeds of Podocarpus nagi, together with three known compounds. The structures of the new compounds were elucidated by extensive analysis of NMR and HR-ESIMS data. All the new compounds were tested for nitric oxide (NO) inhibitory activities on lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Compound 1 significantly inhibited NO production with IC₅₀ value of 5.38 ± 0.17 μM, and suppressed inducible NO synthase (iNOS) expression in a dose-dependent manner, which were mediated through inhibiting the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) activation.     

Bioactive secondary metabolites from the marine-associated fungus Aspergillus terreus

Three new compounds, including a prenylated tryptophan derivative, luteoride E (1), a butenolide derivative, versicolactone G (2), and a linear aliphatic alcohol, (3E,7E)-4,8-dimethyl-undecane-3,7-diene-1,11-diol (3), together with nine known compounds (4–12), were isolated and identified from a coral-associated fungus Aspergillus terreus. Their structures were elucidated by HRESIMS, one- and two-dimensional NMR analysis, and the absolute configuration of 2 was determined by comparison of its electronic circular dichroism (ECD) spectrum with the literature. Structurally, compound 1 featured an unusual (E)-oxime group, which occurred rarely in natural products. Compounds 1–3 were evaluated for the α-glucosidase inhibitory activity, and compound 2 showed potent inhibitory potency with IC₅₀ value of 104.8 ± 9.5 μM, which was lower than the positive control acarbose (IC₅₀ = 154.7 ± 8.1 µM). Additionally, all the isolated compounds were evaluated for the anti-inflammatory activity against NO production, and compounds 1–3, 5–7, and 10 showed significant inhibitory potency with IC₅₀ values ranging from 5.48 to 29.34 μM.     

Hypocreaterpenes A and B,cadinane-type sesquiterpenes from a marine-derived fungus,Hypocreales sp.

Two new cadinane-type sesquiterpenes, hypocreaterpenes A (1) and B (2), along with five known compounds (3–7) were isolated from a marine-derived fungus Hypocreales sp. strain HLS-104 isolated from a sponge Gelliodes carnosa. Their structures were determined by a combination of spectroscopic methods. All compounds were tested for the inhibitory effects on the nitric oxide (NO) production in lipopolysaccharide (LPS)-treated RAW264.7 cells. Among them, compounds 3 and 6 showed moderate anti-inflammatory activity with average maximum inhibition (E_max) values of 10.22% and 26.46% at 1 μM, respectively.     

Flavonoid glycosides from Barringtonia acutangula

Using various chromatographic separation techniques, ten flavonoid glycosides, including six new compounds namely barringosides A?F (1–6), were isolated from a methanol extract of the Barringtonia acutangula leaves. The structure elucidation was confirmed by spectroscopic analyses, including 1D and 2D NMR, and HR ESI MS. Their inhibitory effects on LPS-induced NO production in RAW264.7 cells were also evaluated. Among the isolated compounds, quercetin 3-O-β-d-(6-p-hydroxybenzoyl)galactopyranoside (9) showed significant effect with an IC₅₀ of 20.00 ± 1.68 µM. This is the first report of these flavonoid glycosides from Barringtonia genus and their inhibition on LPS-induced NO production in RAW264.7 cells was reported here for the first time.     

Bioactivity-based analysis and chemical characterization of anti-inflammatory compounds from Curcuma zedoaria rhizomes using LPS-stimulated RAW264.7 cells

Inflammation is not only a self-defense response of the innate immune system, but also the pathogenesis mechanism of multiple diseases such as arthritis, neurodegeneration, and cancer. Curcuma zedoaria Roscoe (Zingiberaceae), an indigenous plant of India, has been used traditionally in Ayurveda and folk medicine. As part of our ongoing efforts to screen traditional medicinal plants exhibiting pharmacological potential and to characterize the compounds involved, we examined the anti-inflammatory effects of the MeOH extract of C. zedoaria rhizomes using lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells and found that MeOH extract inhibited the synthesis of nitric oxide (NO) in a dose-dependent manner (IC₅₀: 23.44 ± 0.77 μg/mL). In our efforts to characterize the compounds responsible for these anti-inflammatory effects, bioactivity-guided fractionation of the MeOH extract and chemical investigation of its active hexane-soluble fraction led to the successful isolation of five sesquiterpenes (1–5), the structures of which were elucidated by NMR spectroscopic analysis and LC/MS analysis. Among them, curcuzedoalide (5) exhibited potent inhibitory effects on NO synthesis (IC₅₀: 12.21 ± 1.67 μM) and also suppressed pre-inflammatory protein expression of iNOS and COX-2. Curcuzedoalide (5) was thus determined to be a contributor to the anti-inflammatory effect of C. zedoaria rhizomes and could be a potential candidate for therapeutic applications.     

C19-Diterpenoid alkaloids from Aconitum richardsonianum

Three new aconitine-type C₁₉-diterpenoid alkaloids, richardsonines A-C (1–3), were isolated from the roots of Aconitum richardsonianum Lauener, together with seventeen known compounds (4–20). Their structures were elucidated by extensive spectroscopic analysis, and the absolute stereochemistry of 1 was confirmed by X-ray crystallography. Compounds 2, 5, 8 and 9 were rare C₁₉-diterpenoid alkaloids bearing an OH group at C-16. Isolated compounds were evaluated for inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated neuroinflammatory responses in BV-2 microglial cells. Compounds 3 and 7 showed weak antineuroinflammatory effects with inhibition rates of 35.32 ± 2.29% and 39.94 ± 2.50%, respectively, at a concentration of 100 µM.     

Synthesis, in vitro and in vivo biological evaluation,COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives

The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a–j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5?h of carrageenan injection at the 30?mg?kg^?1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.     

Bioactive chemical constituents from the root bark of Morus australis

Two new pyranoflavonoids, morustralins A (1) and B (2), a new natural benzene derivative, one benzenoid (Z)-1-hydroxy-4-(2-nitroethenyl)benzene (3), and thirty known compounds were isolated and characterized from the root bark of Morus australis. The structures of the new compounds were established from spectroscopic and spectrometric analyses. Ten isolates (1–10) were examined for inhibitory effects on adenosine diphosphate (ADP)-, arachidonic acid (AA)-, and platelet-aggregating factor (PAF)-induced platelet aggregation. Among the tested compounds, compound 3 displayed the most significant inhibition of ADP- and AA-induced platelet aggregation with IC₅₀ values of 9.76 ± 5.54 and 9.81 ± 2.7 μM, respectively. In addition, eight purified compounds (3–10) were examined for inhibition of nitric oxide (NO) production in RAW 264.7 cells and six compounds (3–8) displayed significant inhibitory effects with IC₅₀ values ranging from 2.1 ± 0.3 to 6.3 ± 0.6 μM.     

Neolignan and monoterpene glycoside from the seeds of Pharbitis nil

Phytochemical investigation of an EtOH extract of Pharbitis nil seeds (Convolvulaceae) resulted in the isolation and identification of a new neolignan, 7R,8S-threo-dihydroxydehydrodiconiferyl alcohol (1), and a new monoterpene glycoside, (3Z,7S)-7-hydroxy-3,7-dimethyl-3,8-octadienyl-β-d-glucopyranoside (2), together with a known compound, ethyl α-l-arabinofuranoside (3). The chemical structures of these compounds were unambiguously determined using physical data, HR-ESI–MS and spectroscopic evidence, including 1D and 2D NMR experiments. The anti-inflammatory activities of the isolates were evaluated by estimating the inhibition of nitric oxide (NO) production. Compounds 1 and 2 reduced NO levels in lipopolysaccharide (LPS)-stimulated murine microglial BV-2 cells. In addition, compound 2 showed weak cytotoxicity against the HCT-15 cell line with an IC₅₀ value of 28.6 μM.     

New phenolic cinnamic acid derivatives as selective COX-2 inhibitors. Design,synthesis, biological activity and structure-activity relationships

Selective inhibition of cyclooxygenase (COX)-2 enzyme is an important achievement when looking for potent anti-inflammatory agents, with fewer gastrointestinal side effects. In this work, a new series of cinnamic acid derivatives, namely hexylamides, have been designed, synthesized and evaluated in human blood for their inhibitory activity of COX-1 and COX-2 enzymes. From this, new structure-activity relationships were built, showing that phenolic hydroxyl groups are essential for both COX-1 and COX-2 inhibition. Furthermore, the presence of bulky hydrophobic di-tert-butyl groups in the phenyl ring strongly contributes for selective COX-2 inhibition. In addition, a correlation with the theoretical log P has been carried out, showing that lipophilicity is particularly important for COX-2 inhibition. Further, a plasma protein binding (PPB) prediction has been performed revealing that PPB seems to have no influence in the activity of the studied compounds. From the whole study, effective selective inhibitors of COX-2 were found, namely compound 9 (IC₅₀ = 3.0 ± 0.3 μM), 10 (IC₅₀ = 2.4 ± 0.6 μM) and 23 (IC₅₀ = 1.09 ± 0.09 μM). Those can be considered starting point hit compounds for further optimization as potential non-steroidal anti-inflammatory drugs.     

Synthesis and in vitro evaluation of homoisoflavonoids as potent inhibitors of nitric oxide production in RAW-264.7 cells

Syntheses of natural homoisoflavonoids, (±)-portulacanones A–C (4, 8 and 9), portulacanone D (6), isolated from Portulaca oleracea L. (POL) and their derivatives (3, 5 and 7) have been achieved for the first time along with the synthesis of known derivatives (1 and 2) and their in vitro inhibitory effect against NO production in LPS-induced RAW-264.7 macrophages was evaluated as an indicator of anti-inflammatory activity. All the compounds tested had a concentration-dependent inhibitory effect on NO production by RAW-264.7 macrophages without obvious cytotoxicity. Compounds 3 (97.2% at 10?μM; IC₅₀?=?1.26?µM) followed by 6 (portulacanone D) (92.5% at 10?μM; IC₅₀?=?2.09?µM), 1 (91.4% at 10?μM; IC₅₀?=?1.75?µM) and 7 (83.0% at 10?μM; IC₅₀?=?2.91?µM) were the most potent from the series. This finding was further correlated with the suppressed expression of iNOS induced by LPS. Our promising preliminary results may provide the basis for the assessment of compound 3 as a lead structure for a NO production-targeted anti-inflammatory drug development and also could support the usefulness of POL as a folklore medicinal plant in the treatment of inflammatory diseases.     

Anti-inflammatory activity of halogenated secondary metabolites of Laurencia snackeyi (Weber-van Bosse) Masuda in LPS-stimulated RAW 264.7 macrophages

Secondary metabolites of tropical seaweed are proven to exhibit variety of biological activities. Six species of seaweed (Caulerpa racemosa var. laete-virens, Caulerpa sertularioides f. longipes, Halymenia dilatata, Laurencia snackeyi, Padina boryana, and Sargassum swartzii) were tested for anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Crude L. snackeyi extract exhibit potent activity, and upon bioassay-guided isolation, it contained four halogenated compounds that exert profound inhibitory effects against nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells. These compounds were subjected to spectroscopic measurements and were identified as palisadin A (1), aplysistatin (2), 5-acetoxypalisadin B (3), and palisol (4). Further experiments showed aplysistatin (2) to significantly inhibit NO production and prostaglandin-E2 (PGE2) production, and suppress inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in LPS-stimulated RAW 264.7 cells. Therefore, aplysistatin (2) is suggested to inhibit NO and PGE2 production via the inhibition of iNOS and COX-2, indicating that its activity may be attributed to the modulation of anti-inflammatory agents.     

New lignan glycosides from the root barks of Litsea glutinosa

An investigation on the chemical constituents in the root barks of Litsea glutinosa was performed for the first time. Three new lignan glycosides named Litseasins A–C (1–3), together with a known one (4), were obtained. The structures of the new compounds were established through extensive spectroscopic analyses including HR-ESI–MS, NMR, and circluar dichroism (CD). The new compounds were evaluated for their anti-inflammatory activities on lipopolysaccharide (LPS)-induce nitric oxide (NO) production in RAW264.7 murine macrophage cells. However, these compounds showed no inhibition on LPS-induced NO productions.