Beilschglabrines A and B: Two new bioactive phenanthrene alkaloids from the stem bark of Beilschmiedia glabra

Two new phenanthrene alkaloids, beilschglabrines A (1) and B (2) were isolated from the stem bark of Beilschmiedia glabra, together with lupeol, taraxerol, and 24-methylenelanosta-7,9-diene-3β-15α-diol. The structures of the isolated compounds were elucidated by extensive spectroscopic data analysis and comparison with respective literature data. The compounds were tested for DPPH radical scavenging, acetylcholinesterase and lipoxygenase inhibitory activities. Compound 1 displayed considerable activity in the acetylcholinesterase (IC₅₀ 50.4 μM), the DPPH radical scavenging (IC₅₀ 115.9 μM) and the lipoxygenase (IC₅₀ 32.8 μM) assays.     

Flavonoids and other bioactive constituents from Ficus thonningii Blume (Moraceae)

Continued interest in the chemistry of Ficus spp. led to the investigation of the figs and the roots of Ficus thonningii Blume. Two new flavonoids, thonningiol (1) and thonningiisoflavone (2) along with nineteen known compounds were isolated. β-Isoluteone (13) was isolated here for the first time from a natural source. Their structures were elucidated on the basis of spectroscopic evidence. Interestingly, thonningiisoflavone (2) and hydroxyalpinumisoflavone (21) showed strong DPPH radical scavenging activity with IC₅₀ = 65.50 μM and 68.20 μM respectively compared to the standard BHA with IC₅₀ = 44.20 μM. The methanolic extract of figs, taxifolin (14), conrauiflavonol (17) and shuterin (19) exhibited moderate antimicrobial activity against six micro-organisms with MIC below 1.5 mg/mL.     

Nitric oxide inhibitory principles from Derris trifoliata stems

Nine rotenoids were isolated from the hexane and dichloromethane extracts of Derris trifoliata stems and were tested for nitric oxide (NO) inhibitory activity using RAW264.7 cells. The result indicated that 12a-hydroxyrotenone (7) possessed very potent NO inhibitory activity with an IC₅₀ value of 0.002 μM, followed by 1 (deguelin, IC₅₀=0.008 μM), 9 (12a-hydroxyelliptone, IC₅₀=0.010 μM) and 2 (α-toxicarol, IC₅₀=0.013 μM), respectively. In addition, the DPPH scavenging activity of rotenoids was also investigated. It was found that 6a,12a-dehydrodeguelin (5) possessed the highest activity against DPPH with an IC₅₀ value of 7.4 μM, followed by deguelin (1, IC₅₀=27.4 μM). All compounds did not show any cytotoxicity at their IC₅₀ values for NO inhibitory activity.Structure–activity relationships (SARs) of these rotenoids against NO release are as follows: (1) hydroxylation at C12a dramatically increased activity, (2) prenylation at furan ring increased activity markedly and (3) hydrogenation of a double bond at C6a–C12a conferred higher activity. For the DPPH radical scavenging effect, it was found that (1) introduction of a double bond at C6a–C12a increased activity and (2) hydroxylation of C11 at the D-ring decreased activity. As regards active compounds of Derris trifoliata stems, the isolated compounds are responsible for the NO inhibitory effect, especially 7, 1, 9 and 2, whereas 5 and 1 are those for the DPPH scavenging activity.     

Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Terpenoids with cytotoxic activity from the branches and leaves of Pyrus pashia

Twenty terpenoids, including a new triterpenoid (1) and a new monoterpenoid (20), were isolated from the branches and leaves of Pyrus pashia. The structures of two new compounds were determined to be 2α, 3β, 27-trihydroxyolean-12-en-28-oic acid (1) and (4α)-3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol 3-O-β-d-glucopyranoside (20) on the basis of spectroscopic analysis (IR, HRESIMS, 1D and 2D NMR) and chemical method. Some of the isolated compounds were evaluated for their cytotoxic activity against a panel of human cancer cell lines by MTT assay, using cisplatin as a positive control. Compound 14 exhibited cytotoxic activities against A549 (IC₅₀ = 19.18 ± 4.26 μM), Hela (IC₅₀ = 12.56 ± 3.89 μM), SGC7901 (IC₅₀ = 10.48 ± 1.95 μM) and NHI-1975 (IC₅₀ = 7.38 ± 2.31 μM) cell lines as well as compound 12 displayed cytotoxic activities against A549 (IC₅₀ = 14.71 ± 1.47 μM) and Hela (IC₅₀ = 12.22 ± 1.88 μM) cell lines.     

Design,synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies

A new series, 2-substituted mercapto-3-[2-(pyridin-2-yl)ethyl]-4(3H)-quinazolinone 1–21, was synthesized and evaluated for in vivo anti-inflammatory and analgesic activities and in vitro COX-1/COX-2 inhibition. Compounds 1, 4, 5, 6, 8, 10, 13, 14, 15, 16, and 17 exhibited potent anti-inflammatory and analgesic properties, with ED₅₀ values of 50.3–112.1 mg/kg and 12.3–111.3 mg/kg, respectively. These values may be compared with those of diclofenac sodium (ED₅₀ = 112.2 and 100.4 mg/kg) and celecoxib (ED₅₀ = 84.3 and 71.6 mg/kg). Compounds 4 and 6 possessed strong COX-2 inhibitory activity with IC₅₀ (0.33 μM and 0.40 μM, respectively) and selectivity index (SI > 303.0 and >250.0, respectively) values that are similar to those of the reference drug celecoxib (IC₅₀ 0.30 μM and COX-2 SI > 333). Compounds 5, 8, and 13 demonstrated effective COX-2 inhibitory activity with IC₅₀ values of 0.70–0.80 μM and COX-2 SI > 125–142. Potent COX-2 inhibitors, such as compounds 4, 6, and 13, were docked into the active site pockets of COX-1 and COX-2, with the greatest recognition occurring at the COX-2 binding site and insignificant interactions at the binding site of the COX-1 pocket.     

Synthesis and SAR study of 4,5-diaryl-1H-imidazole-2(3H)-thione derivatives,as potent 15-lipoxygenase inhibitors

A series of 4,5-diaryl-1H-imidazole-2(3H)-thione was synthesized and their inhibitory potency against soybean 15-lipoxygenase and free radical scavenging activities were determined. Compound 11 showed the best IC₅₀ for 15-LOX inhibition (IC₅₀ = 4.7 μM) and free radical scavenging activity (IC₅₀ = 14 μM). Methylation of SH at C₂ position of imidazole has dramatically decreased the 15-LOX inhibition and radical scavenging activity as it can be observed in the inactive compound 14 (IC₅₀ >250 μM). Structure activity similarity (SAS) showed that the most important chemical modification in this series was methylation of SH group and Docking studies revealed a proper orientation for SH group towards Fe core of the 15-LOX active site. Therefore it was concluded that iron chelating could be a possible mechanism for enzyme inhibition in this series of compounds.     

Synthesis,biological evaluation,and docking studies of novel heterocyclic diaryl compounds as selective COX-2 inhibitors

Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC₅₀ = 0.061 μM and COX-2 IC₅₀ = 0.325 μM; selectivity index (SI) = 0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC₅₀ = 0.011 μM and 0.398 μM, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC₅₀ = 1 μM, COX-2 IC₅₀ = 0.011 μM; SI = ～92). Molecular docking studies of compounds 6b and 11b–d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors.     

Cytotoxic activity of butane type of 1,7-seco-2,7′-cyclolignanes and apoptosis induction by Caspase 9 and 3

All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7′-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC₅₀ = 16–20 μM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (−)-Kadangustin J showed stereospecific cytotoxic activity (IC₅₀ = 47–67 μM). Since (R)-9′-fluoro derivative 23 was most potent (IC₅₀ = 19 μM) among the corresponding fluoro stereoisomers, (R)-9′-alkyl derivatives were synthesized, hydrophobic 9′-heptyl derivative 27 showing highest activity (IC₅₀ = 3.7 μM against HL-60, IC₅₀ = 3.1 μM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9′-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay.     

Design,synthesis, and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors

Four series of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (12a–e, 13a–f, 14a–f and 15a–i) were designed, synthesized and evaluated for the IC₅₀ values against three cancer cell lines (A549, PC-3 and MCF-7) and c-Met kinase. Five selected compounds (13b, 15b, 15d, 15e and 15f) were further evaluated for the activity against HepG2 and Hela cell lines. Eighteen of the compounds showed excellent cytotoxicity activity and selectivity with the IC₅₀ valuables in single-digit μM to nanomole range. Seven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15f showed superior activity to Foretinib, with the IC₅₀ values of 1.04 ± 0.11 μM, 0.02 ± 0.01 μM and 9.11 ± 0.55 μM against A549, PC-3 and MCF-7 cell lines, which were 0.62 to 19.5 times more active than Foretinib (IC₅₀ values: 0.64 ± 0.26 μM, 0.39 ± 0.11 μM, 9.47 ± 0.22 μM), respectively. Structure–activity relationships (SARs) and docking studies indicated that replacement of quinoline nucleus of the previous active compounds with 1H-pyrrolo[2,3-b]pyridine moiety maintained even improved the potent cytotoxic activity. The results suggested that the introduction of fluoro atoms to the aminophenoxy part of target compounds or the phenyl group of pyrimidine substituted on C-4 position was benefit for the activity.     

Chemical constituents of Ligularia alticola Worosch. leaves and their biological activities

Seven eremophilane-type sesquiterpenes (1–7), six cycloartane derivatives (8–13) and α-amyrin acetate (14) were isolated from the leaves of the far-eastern plant Ligularia alticola Worosch. (Family Asteraceae). (4S,5R,8S,10R)-8-Ethoxyeremophil-7(11)-en-12(8)-olide (1), 8α,11-epidioxy-8β-methoxyeremophil-6-ene (2) and 29-norcycloartan-3α-ol (8) have not been previously reported. Fukinone α-epoxide (3) was isolated for the first time from a natural source. The structures of all the compounds were established by the extensive analysis of their 1D and 2D NMR spectra and HR ESI mass spectrometry. The absolute stereochemistry of 1 was determined by comparison of theoretical and experimental ECD spectra with the application of B3LYP-TDDFT and B3LYP-GIAO calculations as well as by NMR spectroscopy. Compound 1 showed cytotoxic action against human cancer HL-60, Raji, and THP-1 cell lines (IC₅₀ 12.6, 6.0 and 6.9 μM, respectively). Compounds 2 and 4 demonstrated significant cytotoxic activities against HL-60 (IC₅₀ 2.8 and 5.8 μM, respectively) and Raji cells (IC₅₀ 2.9 and 4.2 μM, respectively). Compound 6 was cytotoxic against Raji cells (IC₅₀ 4.6 μM). None of tested compounds were cytotoxic against RAW 264.7 cells. Compounds 1 and 4–7 significantly decreased intracellular ROS levels, induced by endotoxic LPS from Escherichia coli in RAW 264.7 murine macrophages.     

Candenatenins G–K,phenolic compounds from Dalbergia candenatensis heartwood

Five new phenolic compounds, designated candenatenins G–K (1–5), along with four known compounds, were isolated from the heartwood of Dalbergia candenatensis. The structures of these compounds were elucidated by HR-EI-MS, ¹H and ¹³C NMR, COSY, HMQC, HMBC, and NOESY spectra. Compound 5 exhibited potent activity against DPPH radical scavenging with IC₅₀ value of 25.7 μM, whereas compound 2 showed cytotoxicity against NCI-H187 cell line with IC₅₀ value of 14.8 μM.     

New triterpene saponins from the seed cake of Camellia Oleifera and their cytotoxic activity

Two new oleanane-type triterpene saponins, identified as 16α-hydroxy-22-O-angeloyl-23-formyl-28,31-dihydroxymethylene-olean-12-ene-3β-O-{β-d-galactopyranosyl-(1 → 2)[β-d-xylopyranosyl-(1 → 2)-α-l-arabinopyranosyl(1 → 3)]-β-d-glucopyranosiduronic acid} (oleiferasaponin B₁, 1) and 22-O-hydrocinnamoyl-23-formyl-28-dihydroxymethylene-olean-12-ene-3β-O-{β-d-glucopyranosyl-(1 → 2)[β-d-xylopyranosyl-(1 → 2)-α-l-arabinopyranosyl(1 → 3)]-β-d-glucopyranosiduronic acid} (oleiferasaponin B₂, 2), were isolated from the seed cake of Camellia oleifera Abel. Their structures were established by extensive 1D- and 2D-NMR experiments along with TOF-MS analysis and acid hydrolysis. The cytotoxicity of the isolated compounds was evaluated in four human carcinoma cell lines: A 549, SK-OV-3, SK-MEL-2 and HCT15. Both compounds 1 and 2 exhibited significantly cytotoxic activity with IC₅₀ values of 18.5 μM (A549), 11.3 μM (SK-OV-3), 13.9 μM (SK-MEL-2) and 1.6 μM (HCT15) for 1 and IC₅₀ values of 8.4 μM (A549), 6.3 μM (SK-OV-3), 9.2 μM (SK-MEL-2) and 0.8 μM (HCT15) for 2. In addition, compound 2 showed more effective cytotoxic activity than compound 1.     

Cytotoxic triterpene saponins from the stem bark of Kalopanax pictus

Three new compounds, 3β,6β,23-trihydroxyolean-12-en-28-oic acid 3-O-α-l-arabinopyranoside (1), kalopanaxsaponin L (2), and kalopanaxsaponin M (13), as well as eleven known compounds (3–12 and 14), were isolated from the stem bark of Kalopanax pictus. Their structures were determined on the basis of extentive spectroscopic analyses and acid hydrolysis. The cytotoxicity of the compounds was evaluated in three human carcinoma cell lines, including HL-60, HCT-116, and MCF-7. Compounds 1, 5–8, 10, and 11 exhibited significantly cytotoxic activity toward HL-60 cells, with IC₅₀ values ranging from 0.1 to 6.9 μM. Compounds 4–7 and 14 showed significant cytotoxicity against HCT-116 cells, with IC₅₀ values ranging from 0.4 to 9.2 μM. Remarkably, the cytotoxic activities of compounds 5–7 against HCT-116 cells were greater than that of the anticancer chemotherapy drug, mitoxantrone (IC₅₀ = 3.7 μM). Compounds 1, 3, 5, and 14 were cytotoxic toward MCF-7 cells with IC₅₀ values in a range of 7.4–14.5 μM.     

Cytosporone derivatives from the endophytic fungus Phomopsis sp. PSU-H188

Two new cytosporone derivatives (1 and 2) were isolated from the endophytic fungus Phomopsis sp. PSU-H188 together with 19 known compounds. Their structures were elucidated by analysis of spectroscopic data. Known mycoepoxydiene showed potent cytotoxic activity towards both MCF-7 and noncancerous Vero cell lines with the respective IC₅₀ values of 9.27 and 4.06 μM. It exhibited inhibition on glucose output in mouse primary hepatocytes with the IC₅₀ value of 16.06 μM, but did not show cytotoxicity on primary mouse hepatocytes. Additionally, known cytosporone B displayed protective activity against INS-1 832/13 pancreatic β-cells by an EC₅₀ value of 11.08 μM whereas known diaporthalasin displayed antibacterial activity against methicillin-resistant Staphylococcus aureus with an MIC value of 4 μg/mL. Both of them were noncytotoxic to Vero cells.     

Synthesis,biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC₅₀’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC₅₀ = 1.79 μM; COX-1 IC₅₀ >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF₃ substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.     

Three new chlorinated phenolic glycosides from Przewalskia tangutica

Three new chlorinated phenolic glycosides, namely przewatangosides A-C (1-3), along with one known compound, globosumoside A (4), were isolated from the whole plants of Przewalskia tangutica. Their structures were unequivocally determined by extensive spectroscopic analysis and chemical method. The cytotoxic activities of the isolated phenolic glycosides (1-4) were evaluated against the five human cancer cell lines A549, MCF-7, SMMC-7721, HepG2 and HL-60. Przewatangoside A (1) exhibited weak cytotoxicity against SMMC-7721 with the IC₅₀ value of 38.1 μM. All the tested compounds were inactive (IC₅₀ > 50 μM) to the normal human hepatocyte cell line (L02).     

Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design,synthesis, biological evaluation,COX-1,2/5-LOX inhibition and docking study

A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS spectral data and elemental analysis. IC₅₀ values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC₅₀ = 0.67 μM) and 4b (IC₅₀ = 0.58 μM) showed better COX-2 inhibitory activity than celecoxib (IC₅₀ = 0.87 μM) with selectivity index (SI = 8.41, 10.55 in sequent) relative to celecoxib (SI = 8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC₅₀ = 1.92, 2.31 μM) higher than zileuton (IC₅₀ = 2.43 μM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition = 15–20%) at all doses when compared to reference drug celecoxib (% edema inhibition = 15.7–17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site.     

Identification of novel acetylcholinesterase inhibitors: Indolopyrazoline derivatives and molecular docking studies

The synthesis of novel indolopyrazoline derivatives (P1-P4 and Q1-Q4) has been characterized and evaluated as potential anti-Alzheimer agents through in vitro Acetylcholinesterase (AChE) inhibition and radical scavenging activity (antioxidant) studies. Specifically, Q3 shows AChE inhibition (IC₅₀: 0.68 ± 0.13 μM) with strong DPPH and ABTS radical scavenging activity (IC₅₀: 13.77 ± 0.25 μM and IC₅₀: 12.59 ± 0.21 μM), respectively. While P3 exhibited as the second most potent compound with AChE inhibition (IC₅₀: 0.74 ± 0.09 μM) and with DPPH and ABTS radical scavenging activity (IC₅₀: 13.52 ± 0.62 μM and IC₅₀: 13.13 ± 0.85 μM), respectively. Finally, molecular docking studies provided prospective evidence to identify key interactions between the active inhibitors and the AChE that furthermore led us to the identification of plausible binding mode of novel indolopyrazoline derivatives. Additionally, in-silico ADME prediction using QikProp shows that these derivatives fulfilled all the properties of CNS acting drugs. This study confirms the first time reporting of indolopyrazoline derivatives as potential anti-Alzheimer agents.     

Antioxidant aromatic butenolides from an insect-associated Aspergillus iizukae

Four new aromatic butenolides named aspernolides H-K (1–4), along with three known compounds (5–7), were isolated from the metabolites of Aspergillus iizukae, which resided in the guts of cricket species Gryllus testaceus. The structures were elucidated by extensive spectroscopic analysis, modified Mosher methods and Mo₂(OAc)₄-induced electronic circular dichroism (ECD) experiments. Their antioxidant activities were evaluated through ABTS and DPPH radical scavenging assays. Compounds 3, 5, and 7 exhibited significant activities with IC₅₀ values of 29.46, 9.59 and 12.36 μM, respectively, compared with the positive control trolox (IC₅₀ 13.11 μM).