Quantitative Structure–Activity Relationships (QSARs) of Pyrimidine Nucleosides as HIV-1 Antiviral Agents

The structural requirements for the antiviral activity of pyrimidine nucleosides against HIV-1 virus was evaluated with the Hansch SAR analysis. Antiviral activity is best related to the hydrophobicity and steric (L and B3) properties of the substituent at the C5 of pyrimidine ring. Further, the antiviral activity is related to B4 of the substituent at position 3' of the sugar ring with a positive slope. The activity of both uracil and cytosine derivatives can be related to their structure by the same equations, which indicates that the SARs are similar in these two groups of congeners. These results suggest that compounds with a small substituent at the 5 position of the pyrimidine ring and a flat substituent at the 3' position of the sugar ring will be the most active compounds against HIV-1 virus.     

Antimykotische Wirkstoffe, 7. Mitt. Kernsubstituierte N-(1-Adamantyl)-N′-phenylthioharnstoffe

Antimycotic Agents, VII: N-(1-Adamantyl)-N′-phenylthiourea Derivatives with Substituents on the Aromatic Nucleus N-(1-Adamantyl)-N′-phenylthiourea derivatives 3 carrying methylthio groups, fluorine atoms or a trifluoromethyl substituent on the aromatic nucleus may be obtained by nucleophilic addition of an appropriately substituted aniline derivative 2 to (1-adamantyl) isothiocyanate ( 1 ).     

Synthesis and antifungal activity of novel 7-<Emphasis Type="Italic">O</Emphasis>-substituted pyridyl-4-methyl coumarin derivatives

A new series of 7-O-substituted pyridyl-4-methyl coumarin derivatives were synthesized and characterized based on their spectral data. All the target compounds were evaluated for their in vitro antifungal activity against eight important fungal pathogens. This study showed that the introduction of the substituted pyridyl moiety at the 7-hydroxy position of coumarin could enhance the antifungal activities. It also indicated that a bulky substituent was not beneficial to the antifungal activity of those coumarin derivatives.     

Design,Synthesis, Anti‐Tobacco Mosaic Virus (TMV) Activity,and SARs of 7‐Methoxycryptopleurine Derivatives

A series of 7‐methoxycryptopleurine derivatives 2 – 23 were prepared and evaluated for their antiviral activity against tobacco mosaic virus (TMV) for the first time. The bioassay results showed that most of these compounds exhibited excellent in vivo anti‐TMV activity, of which 7‐methoxycryptopleurine salt derivatives 16 , 19, and 23 displayed significantly higher activity than 7‐methoxycryptopleurine ( 1 ) and commercial ribavirin and ningnanmycin. Salification, the most commonly employed method for modifying physical‐chemical properties, did significantly increase antiviral activity, and different salt forms displayed different antiviral effect. This study provides fundamental support for development and optimization of phenanthroquinolizidine alkaloids as potential inhibitors of plant virus.     

Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

Flavonoids are conjugated by phase II enzymes in humans to form glucuronidated and sulfated metabolites that are excreted in urine via the kidney. In this study, we examined the interaction between metabolites of quercetin and isoflavonoids found in vivo with human organic anion transporters 1 (OAT1) and 3 (OAT3) and their potential in attenuating OAT-induced cytotoxicity of adefovir. Accumulation of flavonoid conjugates was studied in human embryonic kidney 293H cells overexpressing OAT1 or OAT3. OAT1-overexpressing cells exhibited an increased uptake of the sulfated conjugates, genistein-4′-O-sulfate and quercetin-3′-O-sulfate. OAT3-overexpressing cells demonstrated enhanced uptake of glucuronide conjugates, such as daidzein-7-O-glucuronide, genistein-7-O-glucuronide, glycitein-7-O-glucuronide and quercetin-3′-O-glucuronide. Position of conjugation was important since quercetin-3-O-glucuronide and quercetin-7-O-glucuronide were poorly transported. Kinetic analysis revealed high affinity uptake of quercetin-3′-O-sulfate by OAT1 (K_m = 1.73 μM; V_max = 105 pmol/min/mg). OAT3 transported isoflavone glucuronides with lower affinity (K_m = 7.9–19.1 μM) but with higher V_max (171–420 pmol/min/mg). Quercetin-3′-O-sulfate strongly inhibited OAT1-mediated p-aminohippuric acid uptake with an IC₅₀ of 1.22 μM. Transport of 5-carboxyfluorescein by OAT3 was potently inhibited by quercetin-3-O-glucuronide, quercetin-3′-O-glucuronide and quercetin-3′-O-sulfate (IC₅₀ = 0.43–1.31 μM). In addition, quercetin-3′-O-sulfate was shown to effectively reduce OAT1-mediated cytotoxicity of adefovir, an antiviral drug, in a dose-dependent manner. These data suggest that OAT1 and OAT3 are responsible for basolateral uptake of flavonoid conjugates in kidney, and flavonoid conjugates inhibit OAT1 and OAT3 activity at physiologically relevant concentrations. Interaction with OATs limits systemic availability of flavonoids and may be a mechanism of food–drug interaction via inhibition of renal uptake.     

Free radical scavengers from the aerial parts of <Emphasis Type="Italic">Euphorbia petiolata</Emphasis>

Reversed-phase preparative high-performance liquid chromatography (HPLC) of the methanol extract of the aerial parts of Euphorbia petiolata Banks & Soland, an endemic Iranian medicinal plant, yielded ten free radical scavengers including eight flavonoid glycosides myricetin 3-O-glucoside (1), kaempferol 3-O-(2-O-galloyl)-glucoside (2), myricetin 3-O-rhamnoside (3), quercetin 3-O-glucoside (4), kaempferol 3-O-glucoside (5), quercetin 3-O-rhamnoside (6), kaempferol 3-O-rhamnoside (7), and quercetin 3-O-rutinoside (10), a coumarin esculetin (8) and a phenylpropanoid 2-hydroxydihydrocinnamic acid (9). The structures of these compounds were elucidated conclusively by spectroscopic means and also by direct comparison of their spectroscopic data with respective published data. The free radical scavenging properties of these compounds were assessed by the 2,2-diphenyl-1-picrylhydrazyl assay.     

Phenolic and Terpenoid Constituents from the Sri Lankan Medicinal Plant Osbeckia aspera.

Abstract

A crude aqueous acetone extract of Osbeckia aspera. Blume (Melastomataceae), a plant from Sri Lanka used traditionally to treat liver disease, was fractionated by column and preparative paper chromatography, and the fractions were analyzed by high-performance liquid chromatography (HPLC) using diode array and mass spectrometric detection. Phenolic acids (gallic, protocatechuic, and ellagic acid), flavonol glycosides [quercetin 3-O.-β-galactopyranoside, quercetin 3-O.-β-glucopyranoside, kaempferol 3-O.-β-glucopyranoside, and kaempferol 3-O.-(6″-O.-p.-coumaroyl-β-glucopyranoside) (tiliroside)] and flavonol aglycones (quercetin and kaempferol) were identified by comparison of their retention times, UV and MS spectra with those of authentic standards. Five compounds from a methanol extract were identified by NMR spectroscopy as the flavonol glycosides, quercetin 3-O.-(3″-O.-acetyl-β-galactopyranoside) and kaempferol 3-O.-[2″,6″-di-O.-(E.,E.)-p.-coumaroyl-β-glucopyranoside], and the norsesquiterpenoids 6,9-dihydroxy-4,7-megastig-madien-3-one, 9-hydroxy-4,7-megastigmadien-3-one and 9-hydroxy-4-megastigmen-3-one. A crude water extract, 50% acetone extract and fractions from this extract, a 100% methanol extract, and three of the phenolic acids in the fractions were tested for in vitro. hepatoprotective activity against bromobenzene and 2,6-dimethyl-N.-acetyl p.-quinoneimine toxicity to HepG2 liver-derived cells. The crude water extract showed protective activity against both liver toxins, whereas the fractions and compounds were more protective against 2,6-dimethyl-N.-acetyl p.-quinoneimine than bromobenzene. Of the three phenolic acids present in the extracts that were tested, gallic and protocatechuic acids were more active at protecting the liver cells from the two toxic compounds than ellagic acid.     

New benzophenone and quercetin galloyl glycosides from <Emphasis Type="Italic">Psidium guajava</Emphasis> L.

New benzophenone and flavonol galloyl glycosides were isolated from an 80% MeOH extract of Psidium guajava L. (Myrtaceae) together with five known quercetin glycosides. The structures of the novel glycosides were elucidated to be 2,4,6-trihydroxybenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (1, guavinoside A), 2,4,6-trihydroxy-3,5-dimethylbenzophenone 4-O-(6″-O-galloyl)-β-d-glucopyranoside (2, guavinoside B), and quercetin 3-O-(5″-O-galloyl)-α-l-arabinofuranoside (3, guavinoside C) by NMR, MS, UV, and IR spectroscopies. Isolated phenolic glycosides showed significant inhibitory activities against histamine release from rat peritoneal mast cells, and nitric oxide production from a murine macrophage-like cell line, RAW 264.7.     

Simple but highly effective three-dimensional chemical-feature-based pharmacophore model for diketo acid derivatives as hepatitis C virus RNA-dependent RNA polymerase inhibitors

A molecular modeling strategy using aryl diketo acid (ADK) derivatives recently reported in the literature as hepatitis C virus (HCV) polymerase inhibitors was designed. A 3D chemical-feature-based pharmacophore model was developed using Catalyst software, which produced 10 pharmacophore hypotheses. The top-ranked one (Hypo 1), characterized by a high correlation coefficient (r = 0.965), consisted of two hydrogen bond acceptors, one negative ionizable moiety, and two hydrophobic aromatics. This model was used to predict the anti-RNA-dependent RNA polymerase (anti-RdRp) activity of 6-(1-arylmethylpyrrol-2-yl)-1,4-dioxo-5-hexenoic acids and other ADK derivatives previously synthesized in our laboratories as HIV-1 integrase inhibitors. Furthermore, the experimental IC50 values of 9 compounds, tested in vitro against recombinant HCV polymerase, were compared with the corresponding values predicted using Hypo1. A good agreement between experimental and simulated data was obtained. The results demonstrate that the hypothesis derived in this study can be considered to be a useful tool in designing new leads based on ADK scaffolds as HCV RdRp inhibitors.     

Two new flavonoid glycosides from the whole herbs of Hyssopus officinalis

Two new flavonoid glycosides, quercetin 7-O-β-d-apiofuranosyl-(1 → 2)-β-d-xylopyranoside (1) and quercetin 7-O-β-d-apiofuranosyl-(1 → 2)-β-d-xylopyranoside 3′-O-β-d-glucopyranoside (2), together with nine known flavonoids were isolated from the whole herbs of Hyssopus officinalis L. cultivated in Xinjiang Uygur Autonomous Region of China. All structures were characterized by the spectroscopic methods including UV, IR, ESI-MS, 1D, and 2D NMR. Their potent free radical scavenging activity against the stable 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical was evaluated.     

Synthesis of some 5′-amino-2′,5′-dideoxy-5-iodouridine derivatives and their antiviral properties against herpes simples virus

In an attempt to improve the antiviral efficacy of 5′-amino-2′,5′-dideoxy-5-iodouridine (AIdU) the N-acetyl and N,3′-O-diacetyl derivatives were prepared. N-Acetylation of AIdU increased its ability to inhibit the phosphorylation of thymidine by the deoxypyrimidine kinase of herpes simplex virus type 1 (HSV1) while diacetylation had the converse effect. The affinity of the corresponding compounds containing uracil or thymine for virus deoxypyrimidine kinase was also determined. A range of N-acyl-, N-sulphonyl- and N,3′-O-diacyl- derivatives of AIdU were synthesised; enhanced inhibition of deoxypyrimidine kinase by a number of these compounds was observed. The previous observation that 5′-azido-2′,5′-dideoxy-5-iodouridine has antiherpetic activity in vivo led us to investigate its 3′-O-acetyl derivative as well as the corresponding compound containing uracil. None of the derivatives described showed antiviral activity in cell culture against HSV1; acylation failed to enhance the potency of AIdU against HSV1 in vivo.     

Antioxidative compounds from <Emphasis Type="Italic">Quercus salicina</Emphasis> Blume Stem

The chromatographic separation of MeOH extract from the Quercus salicina Blume Stem led to the isolation of five phenolic compounds. Using spectroscopic methods, the structures of these compounds were determined as D-threo-guaiacylglycerol 8-O-β-D-(6′-O-galloyl)glucopyranoside (1), 9-methoxy-D-threo-guaiacylglycerol 8-O-β-D-(6′-O-galloyl)glucopyranoside (2), 6″-O-galloyl salidroside (3), methyl gallate (4), quercetin (5). We measured radical scavenging activity with the DPPH method and the anti-lipid peroxidative efficacy on human LDL with TBARS assay, with the result that all these compounds exhibited the antioxidative activity.     

Antiviral phenolics from Antenoron filiforme var. neofiliforme

Abstract

Two new phenolics, 1,3-di-O-p-coumaroyl-2′,6′-di-O-acetylsucrose (1) and quercetin 3-O-β-D-apiofuranoyl-(1→2)-α-L-rhamnopyranoside (2), along with nine known compounds (3–11), were isolated from the whole plants of Antenoron filiforme var. neofiliforme. Their chemical structures were characterized on the basis of various spectroscopic techniques. This is the first report of the isolation of phenylpropanoid sucrose (1, 3–4) from the genus Antenoron. The bioassay results showed that compound 11 exhibited antiviral activity against the Coxsackie virus B3 (CVB3).     

Simultaneous determination of quercetin and its glycosides from the leaves of <Emphasis Type="Italic">Nelumbo nucifera</Emphasis> by reversed-phase high-performance liquid chromatography

The purpose of this study was to develop reversed-phase HPLC method for the simultaneous determination of the flavonoids from the leaves of Nelumbo nucifera, which have been known to exhibit antioxidant, anti-HIV, antihyperlipidemic and antiobesity effects. HPLC separation was achieved on C₁₈ column using gradient elution with mobile phase consisting of acetonitrile-water containing 0.1% formic acid. The separated peaks were identified by electrospray ionization mass spectrometry. The HPLC method was validated and applied for the simultaneous determination of the bioactive flavonoids from the leaves of Nelumbo nucifera. In the methanol extract, six flavonoids, quercetin, rutin, quercetin 3-O-β-D-galactopyranoside (Qc-3-Gal), quercetin 3-O-β-D-glucopyranoside (Qc-3-Glc), quercetin 3-O-β-D-glucuronide (Qc-3-Gln) and quercetin 3-O-α-arabinopyranosyl-(1→2)-β-galactopyranoside (Qc-3-AraGal), were identified. Among them, Qc-3-Glc and Qc-3-Gln were found to be major component in the methanol extract of Nelumbo nucifera leaves.     

New iridoid diesters of glucopyranose from Linaria canadensis (L.) Dum.

Two new iridoid diesters of glucopyranose were isolated from the aerial part of Linaria canadensis (L.) Dum. Eight known flavones, apigenin, diosmetin, genkwanin, luteolin, luteolin 7-O-glucoside, luteolin 7-O-glucuronide, genkwanin 4′-O-rutinoside, and quercetin 7-O-rutinoside were also isolated. The chemical structures of the isolated compounds were elucidated based on the analyses of the spectroscopic data.     

Neuroprotective compounds from <Emphasis Type="Italic">Reynoutria sachalinensis</Emphasis>

Glutamate is a neurotransmitter in central nervous system. Overexpression of glutamate leads to oxidative stress, resulting in several neurodegenerative disorders that include Alzheimer’s disease. The n-hexane fraction of stems and ethyl acetate (EtOAc) fraction of flowers of Reynoutria sachalinensis provide neuroprotection against glutamate-induced oxidative toxicity in HT22 cells. In this study, 1-decanol (1), β-amyrin (2), dammaran-3β-ol (3), campesterol (4), daucosterol (5), ergosterol peroxide (6), emodin 8-O-β-d-glucopyranoside (7), quercetin (8) and isoquercitrin (9) were isolated from n-hexane fractions of stems and EtOAc fractions of flowers of R. sachalinensis. Their neuroprotective activity was evaluated by MTT assay. 1-Decanol, campesterol, ergosterol peroxide, quercetin and isoquercitrin exhibited neuroprotective activity. These compounds decreased reactive oxygen species level, showed anti-oxidant activity with DPPH radical and in a H₂O₂ scavenging assay. Therefore, the neuroprotective activity of 1-decanol, campesterol, ergosterol peroxide, quercetin and isoquercitrin are associated with antioxidant activity.     

A new acylated flavonoid glycoside from the flowers of Camellia nitidissima and its effect on the induction of apoptosis in human lymphoma U937 cells

From the EtOH extract of the flowers of Camellia nitidissima Chi, a new acylated flavonoid glycoside, quercetin 7-O-(6″-O-E-caffeoyl)-β-d-glucopyranoside (1), has been isolated, together with three known flavonoids: quercetin (2), quercetin 3-O-β-d-glucopyranoside (3), and quercetin 7-O-β-d-glucopyranoside (4). Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 was shown to inhibit proliferation and to induce apoptosis of human lymphoma U937 cells.     

Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents

Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonyl Δ^βγ sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation.KEY WORDS: Sophocarpinic acid, Matrine, Anti-HCV, Antiviral activity, Structure−activity relationship     

Phytochemical analysis and antioxidant activity of Lycium barbarum (Goji) cultivated in Greece

Context: The fruit of Lycium barbarum L. (Solanaceae), known as goji berry, has been exploited for a long time in traditional Chinese medicine. In recent decades, it has received much attention as one of the trendiest functional foods with a wide array of pharmacological activities in Western diets.

Objective: In this study the phenolic profile and potential antioxidant capacity of Lycium barbarum cultivated in Crete (Greece) were investigated.

Materials and methods: The berries were defatted with hexane and then extracted with dichloromethane and methanol using a Soxhlet apparatus. Furthermore, the methanol extract was fractionated with ethyl acetate and butanol. All fractions/extracts were tested for their antioxidant activity (DPPH, FRAP, chemiluminescence). Folin–Ciocalteu and LC-DAD-MS analyses were utilized for the identification of the phenolic compounds.

Results: The total phenolic content ranged from 14.13?±?0.40 (water fraction) to 109.72?±?4.09 (ethyl acetate fraction) mg gallic acid equivalent/g dry extract. Ethyl acetate extract exhibited the highest scavenging activities determined as EC₅₀ (4.73?±?0.20?mg/mL) and IC₅₀ (0.47?±?0.001?mg/mL) using DPPH and chemiluminescence assays. Seventeen phenolic compounds, including cinnamoylquinic acids and derivatives, hydrocinnamic acids and flavonoid derivatives, were tentatively identified. To the best of our knowledge, quercetin 3-O-hexose coumaric ester and quercetin 3-O-hexose-O-hexose-O-rhamnose are reported for the first time in goji berry fruits.

Discussion and conclusion: The results of this study suggest that consumption of goji berry fruits could serve as a potential source of natural antioxidant compounds and that goji berry phenolic extracts could be exploited for nutritional pharmaceutical purposes.