Antiviral activity of raoulic acid from Raoulia australis against Picornaviruses

RNA viruses are a major source of respiratory diseases worldwide. The lack of effective therapeutical treatment underlines the importance of research for new antiviral compounds. Raoulic acid is a principal ingredient of the plant Raoulia australis Hook. F. Antiviral assay using cytopathic effect (CPE) reduction method showed that raoulic acid possessed strong antiviral activity against human rhinovirus 2 (HRV2) with a 50% inhibition concentration (IC₅₀) value of less than 0.1 μg/ml, human rhinovirus 3 (HRV3) with a IC₅₀ value of 0.19 μg/ml, coxsackie B3 (CB3) virus with IC₅₀ values of 0.33 μg/ml, coxsackie B4 (CB4) virus with IC₅₀ values of 0.40 μg/ml, and enterovirus 71 (EV71) virus with IC₅₀ values of less than 0.1 μg/ml. However, the compound did not possess antiviral activity against influenza A (Flu A/PR, Flu A/WS, H1N1) and B viruses at four concentrations ranging from 0.1 to 100 μg/ml.     

Synthesis and radical scavenging activity of phenol–imidazole conjugates

Novel hydroxylated benzylideneamino imidazole derivatives were synthesized and their radical scavenging activity was assessed against DPPH and hydroxyl radicals. In the DPPH assay, most of the synthesized compounds showed an IC₅₀ in the range 3.2 μM ⩽ IC₅₀ ⩽ 8.4 μM, lower than the reference compound trolox (IC₅₀ = 9.5 μM) or the parent aldehydes (5.4 μM ⩽ IC₅₀ ⩽ 11.6 μM). The activity depends mainly on the phenolic subunit (number and position of the hydroxyl groups) and the extent of conjugation with the imidazole ring. In the deoxyribose assay, all the compounds, including parent imidazoles and aldehydes, showed high activity against the hydroxyl radical and the ability to chelate iron ions. At 5 μM concentration, the compounds protected the deoxyribose from degradation by hydroxyl radical between 62% and 38%.     

Biological activities of two macroalgae from Adriatic coast of Montenegro

In the present investigation the acetone extracts of macroalgae Ulva lactuca and Enteromorpha intestinalis were tested for antioxidant, antimicrobial and cytotoxic potential. Antioxidant activity was evaluated by measuring the scavenging capacity of tested samples on DPPH and superoxide anion radicals, reducing the power of samples and determination of total phenolic and flavonoid compounds in extracts. As a result of the study, U. lactuca extract was found to have a better free radical scavenging activity (IC₅₀ = 623.58 μg/ml) than E. intestinalis extract (IC₅₀ = 732.12 μg/ml). Moreover, the tested extracts had effective ferric reducing power and superoxide anion radical scavenging. The total content of phenol in extracts of U. lactuca and E. intestinalis was 58.15 and 40.68 μg PE/mg, while concentrations of flavonoids were 39.58 and 21.74 μg RE/mg, respectively. Furthermore, among the tested species, extracts of U. lactuca showed a better antimicrobial activity with minimum inhibitory concentration values ranging from 0.156 to 5 mg/ml, but it was relatively weak in comparison with standard antibiotics. Bacillus mycoides and Bacillus subtilis were the most susceptible to the tested extracts. Contrary to this Aspergillus flavus, Aspergillus fumigatus and Penicillium purpurescens were the most resistant. Finally, cytotoxic activity of tested extracts was evaluated on four human cancer cell lines. Extract of E. intestinalis expressed the stronger cytotoxic activity towards all tested cell lines with IC₅₀ values ranging from 74.73 to 155.39 μg/ml.     

Synthesis and biological evaluation of novel thiadiazole amides as potent Cdc25B and PTP1B inhibitors

A series of novel thiadiazole amide derivatives have been synthesized and evaluated for inhibitory activities against Cdc25B and PTP1B. Most of them showed inhibitory activities against Cdc25B (IC₅₀ = 1.18–8.01 μg/mL) and PTP1B (IC₅₀ = 0.85–8.75 μg/mL), respectively. Moreover, compounds 5b and 4l were most potent with IC₅₀ values of 1.18 and 0.85 μg/mL for Cdc25B and PTP1B, respectively, compared with reference drugs Na₃VO₄ (IC₅₀ = 0.93 μg/mL) and oleanolic acid (IC₅₀ = 0.85 μg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against PTP1B and Cdc25B. Enzyme kinetic experiments demonstrated that compound 5k was a specific inhibitor with the typical characteristics of a mixed inhibitor.     

Zizimauritic acids A–C,three novel nortriterpenes from Ziziphus mauritiana

Zizimauritic acids A–C (1–3), three novel nortriterpenes with a unique A-nor-E-seco spiro-lactone ceanothane-type triterpene skeleton, together with 3 known triterpenes ceanothenic acid (4), betulinic acid (5), and ceanothic acid (6), were isolated from the roots of Ziziphus mauritiana. Compounds 1–4 showed cytotoxicities with the IC₅₀ values ranging from 5.05 to 11.94 μg/ml, and compounds 1 and 3 showed an inhibitory effect on the growth of Staphylococcus aureus with the IC₅₀ values 2.17 and 12.79 μg/ml. A plausible biosynthetic pathway of compounds 1-3 was proposed.     

New phenolic glycosides with cyclooxygenase inhibition from the roots of Tecoma mollis

Three new phenolic glycosides (1–3) together with nine known ones were isolated from the roots of Tecoma mollis using DPPH radical scavenging bioassay-guided chromatographic separation. The structures of the new compounds were established using extensive spectroscopic data and HR-MS. The antioxidant, COX-2 inhibition, and cytotoxic activities were evaluated for the isolated compounds. Compound 4 displayed the strongest radical scavenging activity relative to ascorbic acid with IC₅₀ 8.7 μM. Compounds 5, 6, and 10 showed promising COX-2 inhibitory action, IC₅₀ values of 11.3 μM, 9.4 μM, and 13.4 μM, respectively. All compounds exhibited weak cytotoxic activity against Hela and A549 cancer cell lines.     

Design,synthesis and anti-Alzheimer properties of dimethylaminomethyl-substituted curcumin derivatives

Eight dimethylaminomethyl-substituted curcumin derivatives were designed and synthesized. The antioxidant test revealed that the synthesized compounds had higher free radical scavenging activity towards both 2,2-diphenyl-1-picrylhydrazyl free radicals (DPPH) (IC₅₀ 1.5–29.9 μM) and galvinoxyl radicals (IC₅₀ 4.9–41.1 μM) than the lead compound curcumin. Besides, compound 3a could effectively inhibit the Aβ self-aggregation in vitro. Investigated in phosphate-buffered solutions (pH = 7.4) in the presence or absence of 0.1% FBS 3a showed a good stability while curcumin did not. Furthermore, 3a showed a good lipophilicity (log P = 3.48), suggesting a potential ability to penetrate the blood–brain-barrier. The aqueous solubility of the hydrochloride salt of 3a (16.7 mg/mL) has also been significantly improved as compared with curcumin (<0.1 mg/mL).     

Inhibition of tyrosinase activity by polyphenol compounds from Flemingia philippinensis roots

Flemingia philippinensis is used as a foodstuff or medicinal plant in the tropical regions of China. The methanol (95%) extract of the roots of this plant showed potent tyrosinase inhibition (80% inhibition at 30 μg/ml). Activity-guided isolation yielded six polyphenols that inhibited both the monophenolase (IC₅₀ = 1.01–18.4 μM) and diphenolase (IC₅₀ = 5.22–84.1 μM) actions of tyrosinase. Compounds 1–6 emerged to be three new polyphenols and three known flavanones, flemichin D, lupinifolin and khonklonginol H. The new compounds (1–3) were identified as dihydrochalcones which we named fleminchalcones (A–C), respectively. The most potent inhibitor, dihydrochalcone (3) showed significant inhibitions against both the monophenolase (IC₅₀ = 1.28 μM) and diphenolase (IC₅₀ = 5.22 μM) activities of tyrosinase. Flavanone (4) possessing a resorcinol group also inhibited monophenolase (IC₅₀ = 1.79 μM) and diphenolase (IC₅₀ = 7.48 μM) significantly. In kinetic studies, all isolated compounds behaved as competitive inhibitors. Fleminchalcone A was found to have simple reversible slow-binding inhibition against monophenolase.     

Chemical composition,angiotensin I-converting enzyme (ACE) inhibitory,antioxidant and antimicrobial activities of the essential oil from south Tunisian Ajuga pseudoiva Rob. Lamiaceae

The essential oil of Ajuga pseudoiva, collected from Tunisia, was analyzed using gas chromatography–mass spectroscopy. Thirty-two compounds accounting for 95.76% of the total oil were identified. Sesquiterpenes were found to be the most abundant components of A. pseudoiva oil. And they were mainly represented by viridiflorol (30.17%), germacrene B (9.26%) (α, β and γ)-eudesmol (8.11%) and aromadendrene (7.45%). The essential oil of A. pseudoiva showed radical scavengers activity (IC₅₀ = 0.72 mg/mL) and displayed lipid peroxidation inhibitory activity (IC₅₀ = 0.6 mg/mL). A. pseudoiva essential oil was also found to exhibit a dose-dependent ACE inhibitory activity with an IC₅₀ value of 65.5 μg/mL. Moreover, the antimicrobial activity of the essential oil was tested against 17 species of microorganisms, and the results obtained showed significant antibacterial activity against the Gram-positive and Gram-negative bacteria, with inhibition zones and minimal inhibitory concentration values of 14–32 mm and 84–137 μg/mL and 6–21 mm and 105–336 μg/mL, respectively. Higher activity was also found against several fungal strains.     

Synthesis,biological evaluation,and molecular docking studies of novel 1,3,4-oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity

1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC₅₀ values of 5.68 μg/ml and 10.21 μg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP–PCR–ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC₅₀ values of 1.2 ± 0.3 μM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell.     

Glutathione S-transferase pi (GST-pi) inhibition and anti-inflammation activity of the ethyl acetate extract of Streptomyces sp. strain MJM 8637

To investigate the anti-cancer properties of soil-borne actinobacteria, MJM 8637, the glutathione S-transferase pi (GST-pi) assay, anti-tumor necrosis factor (TNF)-α assay, the level of antioxidant potential by DPPH radical scavenging activity, NO scavenging activity, and ABTS radical scavenging activity in ethyl acetate extract were determined. The 16S rDNA sequencing analysis revealed that Streptomyces sp. strain MJM 8637, which was isolated from Hambak Mountain, Korea, has 99.5% similarity to Streptomyces atratus strain NBRC 3897. The physiological and the morphological characteristics of the strain MJM 8637 were also identified. The ethyl acetate extract of MJM 8637 inhibited TNF-α production approximately 61.8% at concentration 100 μg/ml. The IC₅₀ value of the strain MJM 8637 extract on GST-pi was identified to be 120.2 ± 1.6 μg/ml. In DPPH, NO, and ABTS radical scavenging assays, the IC₅₀ values of the strain MJM 8637 extract were found to be 977.2 μg/ml, 1143.7 μg/ml, and 454.4 μg/ml, respectively. The ethyl acetate extract of the strain MJM 8637 showed 97.2 ± 1.3% of cell viability at 100 μg/ml in RAW 264.7 cell viability assay. The results obtained from this study suggest that the ethyl acetate extract of Streptomyces sp. strain MJM 8637 could be considered as a potential source of drug for the cancers that have multidrug resistance with its GST-pi inhibition and anti-inflammation activities, and low cytotoxicity.     

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).     

New coumestan and coumaronochromone derivatives from Dalbergia boehmii Taub. (Fabaceae)

Chemical investigation of leaves and heartwood of Dalbergia boehmii resulted in the isolation of two new phenolic compounds, designated dalbergestan (1) and dalbergichromone (2), along with eleven known compounds, carpachromene (3), proanthocyanidin A-2 (4); piceatannol (5); biochanin A (6); macckiain (7); homopterocarpin (8); angolensin (9); medicarpin (10); 2′,7-dihydroxy-4′,5′-dimethoxyisoflavone (11); 2′-methoxyformononetin (12); and genistein (13). The structures of the new compounds were elucidated on the basis of extensive spectroscopic analyses including, IR, UV, 1D and 2D – NMR as well as HRMS data. Some of the isolated compounds were evaluated for their in vitro insulin secretion activity on isolated mice islets, leishmanicidal activity against L. major (DESTO) promastigotes and in vitro cytotoxicity on MCF-7 cell lines. All tested compounds were inactive on glucose-stimulated insulin secretion at stimulatory glucose (20.0 mM) from MIN6 cells. Compounds 3 (IC₅₀, 70.0 μg/ml), 6 (IC₅₀, 60.3 μg/ml), 7 (IC₅₀, 86.5 μg/ml) and 13 (IC₅₀, 62.6 μg/ml) exhibited low leishmanicidal activity while compound 12 (IC₅₀, 56.8 μg/ml) displayed a moderate activity. Compounds 3 and 5 were found to be active against MCF-7 at 50 μM with IC₅₀ value 33.2 ± 3.79 μg/ml and 42.64 ± 5.05 μg/ml respectively.     

Synthesis of N-Mannich bases of berberine linking piperazine moieties revealing anticancer and antioxidant effects

A new Mannich base series of piperazine linked berberine analogues was furnished in this study to screen the antioxidant and anticancer potential of the resultant analogues. Alkoxy group at a C-9 position of berberine was converted to hydroxyl functionality to enhance the ability of final scaffolds binding to the target of drug action mainly through hydrophobic effect, conjugation effect, whereas Mannich base functionality was introduced on the C-12 position of berberine. Scaffolds were investigated for their free radical scavenging antioxidant potential in FRAP and DPPH assay, whereas tested to check their Fe⁺³ reducing power in ABTS assay. The radical scavenging potential of the final derivatives 4a–j was found excellent with IC₅₀s, <13 μg/mL and < 8 μg/mL in DPPH and ABTS assay, respectively, whereas some analogues showed significant Fe⁺³ reducing power with absorption at around 2 nm in the FRAP assay. Anticancer effects of titled compounds were inspected against cervical cancer cell line Hela and Caski adapting SRB assay, in which analogues 4a–j presented <6 μg/mL of IC₅₀s, and >30 of therapeutic indices, thus exerting low cytotoxic values against Malin–Darby canine kidney (MDCK) cell lines at CC₅₀s >125 μg/mL. Hence, from the bioassay outcomes it can be stated that these analogues are dual active agents as the scavengers of reactive oxygen species and inhibitors of the cancerous cells as compounds with halogen functional group have overall good pharmacological potential in assays studied in this research. Correct structure of the final compounds was adequately confirmed on the basis of FT-IR and ¹H NMR as well as elemental analyses.     

Isolation and evaluation of kaempferol glycosides from the fern Neocheiropteris palmatopedata

Kaempferol glycosides, named palmatosides A (1), B (2) and C (3), together with three known kaempferol glycosides, multiflorins A (4) and B (5), and afzelin (6), were isolated from the roots of the fern Neocheiropteris palmatopedata. Palmatosides A (1) and B (2) each possessed an unusual sugar moiety containing a 4,4-dimethyl-3-oxo-butoxy substituent group. The isolated compounds were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activity, nitric oxide (NO) production, aromatase, quinone reductase 2 (QR2) and COX-1/-2 activities. Palmatosides B (2) and C (3) inhibited TNF-α-induced NF-κB activity with IC₅₀ values of 15.7 and 24.1 μM, respectively; multiflorin A (4) inhibited aromatase enzyme with an IC₅₀ value of 15.5 μM; afzelin (6) showed 68.3% inhibition against QR2 at a concentration of 11.5 μg/ml; palmatoside A (1) showed 52% inhibition against COX-1 enzyme at a concentration of 10 μg/ml; and multiflorin B (5) showed 52% inhibition against nitric oxide production at a concentration of 20 μg/ml. In addition, compounds 3–6 were shown to bind QR2 enzyme using LC–MS ultrafiltration binding assay.     

Structural diversity of nucleoside phosphonic acids as a key factor in the discovery of potent inhibitors of rat T-cell lymphoma thymidine phosphorylase

Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC₅₀ values below 1 μM were selected. Out of them, four compounds strongly inhibited the enzyme with IC₅₀ values lying in a range of 11–45 nM. These most potent compounds might be bi-substrate analogues.     

Novel biphenyl bis-sulfonamides as acetyl and butyrylcholinesterase inhibitors: Synthesis,biological evaluation and molecular modeling studies

A series of new biphenyl bis-sulfonamide derivatives 2a–3p were synthesized in good to excellent yield (76–98%). The inhibitory potential of the synthesized compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) was investigated. Most of the screened compounds showed modest in vitro inhibition for both AChE and BChE. Compared to the reference compound eserine (IC₅₀ 0.04 ± 0.0001 μM for AChE) and (IC₅₀ 0.85 ± 0.0001 μM for BChE), the IC₅₀ values of these compounds were ranged from 2.27 ± 0.01 to 123.11 ± 0.04 μM for AChE and 7.74 ± 0.07 to <400 μM for BuChE. Among the tested compounds, 3p was found to be the most potent against AChE (IC₅₀ 2.27 ± 0.01 μM), whereas 3g exhibited the highest inhibition for BChE (IC₅₀ 7.74 ± 0.07 μM). Structure–activity relationship (SAR) of these compounds was developed and elaborated with the help of molecular docking studies.     

Nigrosphaerin A a new isochromene derivative from the endophytic fungus Nigrospora sphaerica

Nigrosphaerin A, a new isochromene derivative (1), was isolated from the endophytic fungus Nigrospora sphaerica and chemically identified as 3-(3,4-dihydroxyphenyl)-4,6,8-trihydroxy-1H-isochromen-1-one-6-O-β-d-glucopyranoside. In addition nineteen known compounds (2–20) were isolated from the same fungus and chemically identified. Compounds (1–3, 5, and 7–16) were isolated for the first time from this fungus. In vitro antileukemic, antileishmanial, antifungal, antibacterial and antimalarial activities of (1–20) were examined. Compounds 5, 7, 9 and 10 showed good antileukemic activity against HL60 cells with IC₅₀ values of 0.03, 0.39, 0.2 and 0.4 μg/mL, respectively and against K562 cells with IC₅₀ values of 0.35, 0.35, 0.49 and 0.01 μg/mL, respectively. Compounds 3, 4 and 6 showed moderate antileishmanial activity with IC₅₀ values of 30.2, 26.4 and 36.4 μg/ml, respectively. Compound 7 showed moderate antifungal activity against Cryptococcus neoformans with IC₅₀ value of 14.8 μg/mL.     

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.     

Acetylcholinesterase inhibitory effects of the bulb of Ammocharis coranica (Amaryllidaceae) and its active constituent lycorine

Ammocharis coranica (Ker-Gawl.) Herb. (Amaryllidaceae) is used in southern Africa for the treatment of mental illnesses. The ethanol extracts of the bulb of A. coranica and its total alkaloids rich fractions were screened for inhibition of acetylcholinesterase enzyme (AChE), which is implicated in the pathophysiology of Alzheimer's disease. The ethanolic extracts significantly inhibited AChE with IC₅₀ value of 14.3 ± 0.50 μg/ml. The basic ethyl acetate and butanol fractions of the crude extracts were the most active against AChE with IC₅₀ values of 43.1 ± 1.22 and 0.05 ± 0.02 μg/ml respectively. Bioassay-guided fractionation of the basic fractions led to the isolation of lycorine and 24-methylenecycloartan-3β-ol. Lycorine which was isolated from both butanol and ethyl acetate fractions had IC₅₀ of 29.3 ± 3.15 μg/ml, while 24-methylenecycloartan-3β-ol was not active.