Anti-influenza effect of the major flavonoids from Salvia plebeia R.Br. via inhibition of influenza H1N1 virus neuraminidase

To determine the compounds responsible for its anti-influenza activities, we isolated the three flavonoids, 6-hydroxyluteolin 7-O-β-d-glucoside (1), nepitrin (2), homoplantaginin (3) from the MeOH extract of Salvia plebeia R.Br. and identified them by comparing the spectroscopic data with that reported in the literature. The contents of the three flavonoids in the whole extract were 108.74 ± 0.95, 46.26 ± 2.19, and 69.35 ± 1.22 mg/g for 6-hydroxyluteolin 7-O-β-d-glucoside, nepitrin, and homoplantaginin, respectively, which demonstrates that they are the major constituents of this plant. The three flavonoids were evaluated for their inhibitory activities against influenza virus H1N1 A/PR/9/34 neuraminidase and H1N1-induced cytopathic effect (CPE) on Madin-Darby canine kidney (MDCK) cells. Our results demonstrated the following arrangement for their anti-influenza activities: nepitrin (2) > 6-hydroxyluteolin 7-O-β-d-glucoside (1) > homoplantaginin (3). The potent inhibitory activities of these flavonoids against influenza suggested their potential to be developed as novel anti-influenza drugs in the future.     

Synthesis and in vitro evaluation of some new pyrimidines and related condensed ring systems as potential anticancer agents

Several new pyrimidines 6–11, 18–20 , furo-, thieno-, and pyrrolo[2,3-d]pyrimidines 3, 8, 12 , triazolo-[4,3-a]pyrimidines 14, 15, 16 and tetrazolo[1,5-a]pyrimidine 17 were prepared from the known intermediate 5-(2-hydroxyethyl)-6-methyl-2-thiouracil ( 2 ). Compound 7 (4-chloro-5-(2-chloroethyl)-2-methylthio-6-methyl-pyrimidine) exhibited weak antitumor activity in vitro.     

Wickerols A and B: novel anti-influenza virus diterpenes produced by Trichoderma atroviride FKI-3849

Wickerols A and B were produced by a fungus, Trichoderma atroviride FKI-3849. Wickerol A showed potent anti-influenza virus activity against strain A/PR/8/34 (H1N1), whereas wickerol B exhibited weaker impact. The anti-influenza virus spectrum between wickerols A and B was different. The cyclization mechanism of the wickerol carbon-skeleton was investigated by incorporation of ¹³C-labeled acetate. A pathway through the verticillyl cation was predicted.     

Synthesis of 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinolines and some related ring systems

Reduction of amides of 8-amino-6-methoxyquinoline over platinum oxide in glacial acetic acid at room temperature affords 2-substituted-5,6-dihydro-8-methoxy-4H-imidazo [4,5,1-ij]-quinolines (I). The method could not be utilized for urea or carbamate derivatives of 8-amino-6-methoxyquinoline. 2-Amino derivatives of I were prepared through the chloro compound obtained from 5,6-dihydro-8-methoxy-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one, (IV). Several related ring systems have also been prepared.     

Diels-Alder adducts of 3-N-substituted derivatives of (−)-Cytisine as influenza A/H1N1 virus inhibitors; stereodifferentiation of antiviral properties and preliminary assessment of action mechanism

The synthesis and anti-influenza activity study of Diels-Alder adducts of 3-N-substituted derivatives of (−)-cytisine with N-substituted maleimides are described. Synthesized compounds were studied for antiviral activity against influenza virus A/California/07/09 (H1N1)pdm09 in MDCK. The values of CC₅₀, IC₅₀ and selectivity indexes (SI) of obtained derivatives were determined. It was shown that anti-influenza activity of ‘α-endo’ adducts is higher (SI of three samples is 79 and higher) than activity of ‘β-endo’ adducts. By means of ‘time-of-addition’ experiment it was established that the leading compound (3aS,4R,8S,12R,12aR,12bS)-10-benzyl-2-phenyloctahydro-1H-4,12a-etheno-8,12-methanopyrrolo[3′,4':3,4]pyrido[1,2-a][1,5]diazocine-1,3,5(4H)-trione (16a) demonstrates anti-influenza activity at the middle and late stages of the virus life cycle. The possibility of interaction of synthesized derivatives with the active sites of the PA_N and PB2 was estimated via in silico approach. The difference in the locations of ‘α-endo’ and ‘β-endo’ adducts in PB2 active site (5JUN) is offered as an explanation of the dependence of their virus-inhibiting properties on stereochemistry.     

Synthesis,antibacterial and antitumor activity of methylpyridinium salts of pyridoxine functionalized 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles

A library of 29 2-amino-6-sulfanylpyridine-3,5-dicarbonitriles functionalized with a pyridoxine moiety was synthesized using a three-component one-pot reaction of aldehyde derivative of pyridoxine, malononitrile, and thiophenol. The obtained bipyridine structures were converted into methylpyridinium salts. Several compounds demonstrated expressed antibacterial activity with MICs (minimum inhibitory concentrations) in the range of 0.5–4?µg/mL against the three studied Gram-positive strains and 8–64?µg/mL against the Gram-negative E. coli strain, which was comparable or better than the activity of the reference antimicrobial agents. At the same time, all the synthesized compounds were inactive against the Gram-negative P. aeruginosa. Several compounds also demonstrated high cytotoxic activity against the studied tumor cells, but without selectivity for the normal HSF (human foreskin fibroblast) cells. Despite the preliminary character of the performed biological studies, the obtained results make the obtained structural chemotype a promising starting point for the design of physiologically active compounds.     

Synthesis and anti-influenza virus activity of tricyclic compounds with a unique amine moiety

Several novel tricyclic compounds with a unique amine moiety (1, 2a--i) were designed and prepared based on the structure of triperiden for the development of anti-influenza virus agents. An in vitro antiviral assay showed that 1-(1-azabicyclo[3.3.0]octan-5-yl)-1-(4-fluorophenyl)-1-(2-tricyclo[3.3.1.1(3.7)]decyl)methan-1-ol hydrochloride (2f) has a potent anti-influenza A virus activity. Furthermore, since 2f was well tolerated in mice, 2f is promising as a novel anti-influenza virus agent for humans.     

Anti-Influenza a virus of a new oligosaccharide citric acid derivative isolated from Vigna angularis (ohwi et ohashi. var. Dainagon) Seeds

A new oligosaccharide citric acid derivative was isolated by hot aqueous extraction at 85?°C from Vigna angularis seeds, and it was purified using anion exchange chromatography DE-52. The structure was inferred by using UV, 1?D and 2?D NMR spectroscopy and HR-MALDI/MS, and identified as α-D-galactopyranosyl-(1→6)-α-D-galactopyranosyl-(1→6)-α-D-glucopyranosyle-(1→2)-β-D-fructofuranosyle citric acid. The isolated oligosaccharide citric acid derivative revealed promising anti-influenza A virus with 50% inhibition concentration (IC₅₀) of 0.162?nM/mL and 50% cytotoxic dose (CC₅₀) of >2.38?nM/mL.     

An Efficient Approach to the Synthesis of Ethyl Esters of 2,6-Anhydro-3-Deoxy-D-Gluco And D-Allo-Heptanoates

ABSTRACT

An efficient synthesis of analogues of DAH (3-deoxy-D-arabino-hept-2-ulosonic acid) and DRH (3-deoxy-D-ribo-hept-2-ulosonic acid) is described. The route exploits a previously published highly double-stereoselective hetero Diels-Alder reaction catalyzed by a chiral salenCo(II) complex. Asymmetric dihydroxylation followed by selective reduction leads to stereoselective introduction of hydroxy groups at C-4 and C-5. Oxidative cleavage of the C-6 side-chain, in situ reduction of the resulting aldehyde and deprotection afford the desired targets, which may be useful precursors to the simple analogues of the anti-influenza agent GG167.     

Neuraminidase inhibitory activity by compounds isolated from aerial parts of Rhinacanthus nasutus

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is known as traditional medicine for the treatment of various diseases, such as cancer, fungal infections, herpes virus infections and several types of skin diseases in South-East Asian countries. In this study, eight compounds 1–8 were isolated from the aerial parts of R. nasutus. The structures of compounds were determined by the spectroscopic methods, including 1D and 2D NMR. The isolated compounds were evaluated for neuraminidase inhibitory activity. Several lignans, 2,3-bis[(4-hydroxy-3,5-dimethoxyphenyl)methyl]-1,4-butanediol (5) and 8,8′-bisdihydrosiringenin glucoside (6), significantly inhibited neuraminidase activity, which was comparable to the positive controls, mangiferin and oseltamivir. In addition, a structure-based virtual screening against neuraminidase using bioactive components was demonstrated.     

Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl₃-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl₃ was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC₅₀ values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.     

Screening and structural characterization of α-glucosidase inhibitors from hawthorn leaf flavonoids extract by ultrafiltration LC-DAD-MS n and SORI-CID FTICR MS

In vitro α-glucosidase inhibition assays and ultrafiltration liquid chromatography with photodiode array detection coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-DAD-ESI-MS ⁿ ) were combined to screen α-glucosidase inhibitors from hawthorn leaf flavonoids extract (HLFE). As a result, four compounds were identified as α-glucosidase inhibitors in the HLFE, and their structures were confirmed to be quercetin-3-O-rha- (1-4)-glc-rha and C-glycosylflavones (vitexin-2″-O-glucoside, vitexin-2″-O-rhamnoside and vitexin) by high-resolution sustained off resonance irradiation collision-induced dissociation (SORI-CID) data obtained by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). Several other C-glycosylflavones (vitexin, isovitexin, orientin, isooriention) and their aglycones apigenin and luteolin were evaluated by in vitro assays, and were found to possess strong α-glucosidase inhibitory activities as well. Moreover, the substituent groups on the flavones had a great impact on the enzyme inhibition activity. C-3′-OH of the B-ring of flavones in particular increased the α-glucosidase inhibition activity, whereas C-glycosylations at C-6 or C-8 of the A ring weakened the inhibition activity.     

大叶橐吾中三个新的艾里莫芬型倍半萜

从大叶橐吾的根部分离得到三个新的艾里莫芬型倍半萜(1, 2和3), 经多种波谱方法和单晶X射线衍射确定它们的结构分别为: 6α,15β-环氧-8β-羟基-艾里莫芬-7(11)-烯-8α,12-内酯(1), 7-乙酰基-13β-羧酸-6(7)-烯-降-艾里莫芬烷(2), 艾里莫芬-7(11)-烯-6α,15β-内酯(3). 此外, 对化合物1进行了抗菌和抗癌活性测试.     

Synthesis of 2-substituted benzylidene-6-b-nitrothiazolo[3,2-α]benzimidazol-3(2H)ones as possible anticonvulsants

Several 2-substituted benzylidene-b-nitrothiazolo[3,2-α]benzimidazol-3(2H)ones were prepared by the condensation of 6-nitrothiazolo[3,2-α]benzimidazol-3(2H)one with suitable aryl aldehydes as possible anticonvulsants. Amongst these benzimidazoles, two compounds possessed anticonvulsant activity and provided 60% protection against pentylene-tetrazol-induced seizures in mice. J. Heterocyclic Chem., 14, 1093 (1977)     

新型胍基葡萄糖苷的合成及生物活性

将2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基异硫氰酸酯(1)与2-氨基-4/6-取代-苯并噻唑(2a~2e)反应, 生成糖基硫脲衍生物(3a~3e), 再在伯胺存在下经氯化汞脱硫, 得到一系列新的多乙酰基胍基糖苷类化合物(4a~4d, 5a~5d, 6a~6d, 7a~7d), 糖基的保护基团在甲醇钠/甲醇条件下脱除. 所有新化合物的结构均经IR, 1H NMR, MS谱和元素分析证实, 所得产物均为β-构型. 生物活性测试结果表明, 化合物4c, 6c, 8b, 8c等对HIV-1蛋白酶表现出了较高的抑制活性; 化合物7c具有抗流感乙型病毒活性; 化合物5e, 7c, 7d等对血管紧张素转化酶具有抑制活性.     

Dibenzo[b,e][1,4]diazepin-1-Ones,Synthesis and Derivatization

Several linearly fused tricyclic 6,7,6-systems were prepared. Reaction of 1,2-diamino-4-nitrobenzene with 5,5-dimethylcyclohexan-1,3-dione gave 3-(2-amino-5-nitroaniIino)-5,5-dimethylcyclohex-2-en-1-one (8) . Reaction of 8 and its analogue 6 with various aldehydes gave 2,3,4₎5,10,11-hexahydro-3,3-dimethyl-11-substituted-1H-dibenzo[b,e][1,4]diazepin-1-ones 9 and 10 . Acetylation of 9 and 10 gave the corresponding N-acetyl derivatives. Spectral data of the products are discussed.     

Pyrimidines. 65. Synthesis of 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-diones

Several 6-substituted thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione derivatives were synthesized. 6-Ethoxycarbonyl derivatives 3 and 7 were prepared by treatment of 6-chloro-5-formyluracil 1 and 6-chloro-5-cyanouracil 6 with ethyl 2-mercaptoacetate in the presence of a base. Electrophilic substitution reactions (Vilsmeier-Haack reaction, bromination, and nitration) of 5,6-unsubstituted thieno[2,3-d]pyrimidine 9 , prepared by condensation of 6-mercaptouracil 8 with chloroacetaldehyde, afforded the corresponding 6-formyl-, 6-bromo-, and 6-nitrothieno[2,3-d]pyrimidines 10, 15 and 16 , respectively.     

Substituted thiosemicarbazido/semicarbazido quinolines as possible antimalarials

Several 2-aryl substituted thiosemicarbazido-4-methyl-6-methoxyquinolines and 2-aryl substituted semi-carbazido 4-methyl-6-methoxyquinolines were synthesized and evaluated for their antimalarial activity in mice infected with Plasmodium berghei. Two of these substituted quinolines were found to exhibit 50% clearance in a dose of 500 mg./kg. administered intraperitoneally for 5 days.     

Arylquinolinecarboxamides: Synthesis,in vitro and in silico studies against Mycobacterium tuberculosis

A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines in five simple and convenient synthetic steps. The structures of all new products were confirmed by routine spectroscopic methods: IR, ¹H and ¹³C NMR, and HRMS (electrospray ionization). The resulting arylquinolinecarboxamides were subjected to biological screening assay for in vitro inhibitory activity against Mycobacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modest antitubercular activity with compounds 8–11 , 15 and 19 exhibiting MIC₉₀ values in the range of 32–85 μM. The antitubercular data suggested that inhibition of Mtb can be imparted by the introduction of a non-polar substituent on C-6 of the quinoline scaffold. Further, to understand the possible mode of action of the series, the reported compounds and bedaquiline were subjected to in silico docking studies against MtbATPase to determine their potential to interfere with the mycobacterial adenosine triphosphate (ATP) synthase. The results showed that these compounds have the potential to serve as antimycobacterial agents. In silico ADME pharmacokinetic prediction results showed the ability of these arylquinolinecarcboxamides to be absorbed, distributed, metabolized and excreted efficiently.     

Aqueous-Mediated green synthesis of novel spiro[indole-quinazoline] derivatives using kit-6 mesoporous silica coated Fe3O4 nanoparticles as catalyst

In this work, a series of eight new spiro[3,4′]1,3-dihydro-2H-indol-2-one-2′-amino-4′,6′,7′,8′-tetrahydro-2′,5’(1’H,3’H)-quinazoline-diones were successfully synthesized through a three-component reaction of 1H-indole-2,3-diones (isatins), guanidine nitrate, and 1,3-cyclohexanediones, by use of Kit-6 mesoporous silica coated Fe₃O₄ nanoparticles (Fe₃O₄@SiO₂@KIT-6) as a highly efficient magnetically separable nanocatalyst in aqueous media at 60°C. Several notable features of thiseco-friendly protocol are high yields of products, short reaction times, operational simplicity, and the use of easily available and recyclable catalyst.