Synthesis and antiviral activity of new 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids derivatives

The synthesis of new 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3a-l) derivatives and the new 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (5a–c) derivatives was achieved with an efficient synthetic route. Ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1) on fusion with appropriate substituted anilines or aminopicolines gave the required new ethyl 4-(phenylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (2a–l) (52–82%) or new ethyl 4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylates (4a–c) (50–60%), respectively. Subsequent hydrolysis of the esters afforded the corresponding carboxylic acids (3a–l) (86–93%) and (5a–c) in high yield (80–93%). Inhibitory effects of 4-(phenylamino)/4-[(methylpyridin-2-yl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acids. Derivatives on Herpes simplex virus type 1 (HSV-1), Mayaro virus (MAY) and vesicular stomatitis virus (VSV) were investigated. Compounds 2d, 3f, 3a, and 3c exhibited antiviral activity against HSV-1, MAY, and VSV virus with EC₅₀ values of 6.8, 2.2, 4.8, 0.52, 2.5, and 1.0. None of these compounds showed toxicity for Vero cells.     

Synthesis, antibacterial, and antifungal activities of biolabile (E)-1-(4-morpholinophenyl)-3-aryl-prop-2-en-1-ones

Abstract  A collection of biolabile (E)-1-(4-morpholinophenyl)-3-aryl-prop-2-en-1-ones 8–13 are synthesized, characterized by melting point, elemental analysis, mass spectroscopy (MS), Fourier-transform infrared (FT-IR), and ¹H and ¹³C nuclear magnetic resonance (NMR) spectroscopic data and evaluated for their in vitro antibacterial and antifungal activities. Compounds 8–13 exerted a wide range of antibacterial activities against all tested Gram-positive and Gram-negative bacterial strains. All the compounds 8–13 were more active against Pseudomonas. Of the synthesized compounds, compounds 9 and 11 exhibited a wide range of antibacterial activities against Staphylococcus aureus, β-Heamolytic streptococcus, Escherichia coli, Klebsiella pneumonia, and Pseudomonas. Compounds 10, 12, and 13 exerted strong antifungal activities against all tested fungal strains, namely Aspergillus flavus, Mucor, Rhizopus, and Microsporum gypsuem. Graphical Abstract        

A new phenylethanoid glycoside from the fruits of <Emphasis Type="Italic">Callicarpa japonica</Emphasis> Thunb. var. <Emphasis Type="Italic">luxurians</Emphasis> Rehd.

A new phenylethanoid glycoside, named acetyl forsythoside B (1), was isolated from the fruits of Callicarpa japonica Thunb. var. luxurians Rehd. (Verbenaceae) along with forsythoside B (2), brandioside (3), poliumoside (4), actioside (5), and apigenin 7-galacturonide (6). The structures of 1–6 were determined on the basis of spectroscopic data. In addition, the antioxidative activity of 1–4 and 6 was evaluated by the ferric thiocyanate method. All of the tested compounds except 6 exhibited almost the same activity as 3-tert-butyl-4-hydroxyanisole. The radical-scavenging effect of 1–6 on the stable free radical 1,1-diphenyl-2-picrylhydrazyl was also examined. Compounds 1–5 showed almost twice the activity compared to α-tocopherol.     

Cytotoxic activities of diarylheptanoids from Alnus japonica

The diarylheptanoids (1–10) 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-glucopyranosyl(1→3)-β-D-xylopyranoside (1), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-O-β-D-apiofuranosyl(1→6)-β-D-glucopyranoside (2), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-5-O-β-D-glucopyranoside (3), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane (4), 1,7-bis-(3,4-dihydroxyphenyl)-heptane-3-one-5-O-β-D-glucopyranoside (5), oregonin (6), hirsutanonol (7), hirsutenone (8), 1,7-bis-(3,4-dihydroxyphenyl)-5-hydroxyheptane-3-O-β-D-xylopyranoside (9), and platyphylloside (10), isolated from the bark of Alnus japonica, were analyzed for their cytotoxic activities on various human and mouse cancer cell lines. The cytotoxic activities of these ten compounds were evaluated against murine B16 melanoma, human SNU-1 gastric cancer, human SNU-354 hepatoma cancer and human SNU-C4 colorectal cell lines. The diarylheptanoids showed potent cytotoxic activities against murine B16 melanoma cells and human SNU-C1 gastric cancer cell when the cell viability was analyzed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide) assay.     

A new <Emphasis Type="Italic">Erythrina</Emphasis> alkaloid from <Emphasis Type="Italic">Erythrina herbacea</Emphasis>

A new Erythrina alkaloid, 10-hydroxy-11-oxoerysotrine (1), has been isolated from the flowers of Erythrina herbacea together with five known compounds: erytharbine (2), 10,11-dioxoerysotrine (3), erythrartine (4), erysotramidine (5) and erysotrine-N-oxide (6). The structure of the new compound was elucidated on the basis of its spectral data, including 2-D NMR and mass (MS) spectra. The new compound is a rare C-10 oxygenated Erythrina alkaloid. The antioxidant activities of the isolated compounds 1–6 were evaluated by scavenging with peroxynitrite.     

New triterpenoid saponins from <Emphasis Type="Italic">Argania spinosa</Emphasis>

Five new triterpene saponins, arganine L (1), O (2), P (3), Q (4) and R (5), were isolated from the barks of Argania spinosa (L.) Skeels. Arganines L-P and R are bidesmosidic saponins. The structures of 1–5 were elucidated as 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-apiofuranosyl-(1–3)-β-d-xylopyranosyl-(1–4)-α-l-rhamnopyranosyl-(1–2)-α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-xylopyranosyl-(1–4)-α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[α-l-arabinopyranosyl] bayogenin, 3-O-[β-d-xylopyranosyl-(1–4)-β-d-glucuronopyranosyl] bayogenin, and 3-O-[β-d-apiofuranosyl-(1–4)-β-d-glucuronopyranosyl]-28-O-[β-d-xylopyranosyl-(1–4)-α-l-rhamnopyranosyl-(1–2)-α-l-arabinopyranosyl] bayogenin, respectively, mainly on the basis of their spectroscopic data.     

Simple and efficient synthetic routes to bioactive s-triazinyl dithiocarbamate derivatives

Series of 2,4-diarylamino-6-[N-(3′-methylphenyl)dithiocarbamoyl]-s-triazines (4a–l) and 2,4-bis[N-(3′-methylphenyl)dithiocarbamoyl]-6-arylamino-s-triazines (7a–l) were synthesized by two different synthetic routes. In the first route (A), 2,4,6-tricholoro-s-triazine (1) was condensed with N-(3-methylphenyl)ammoniumdithiocarbamate to afford compounds 3 or 6, which on reaction with different aryl amines afforded compounds 4a–l or 7a–l. In the second route (B), condensation of 1 with different aryl amines yielded compounds 2a–l or 5a–l. On further treatment with N-(3-methylphenyl)ammoniumdithiocarbamate these afforded compounds 4a–l or 7a–l. The newly synthesized compounds 4a–l and 7a–l were characterized by elemental analyses, infrared (IR), and ¹H nuclear magnetic resonance (NMR) spectroscopic investigation. All the products were evaluated for their antibacterial and antifungal activity.     

三子颗粒下调miR-205-5p抑制小鼠脾虚型肠道腺瘤生长研究

目的 探讨三子颗粒通过降低微小核糖核酸-205-5p（miR-205-5p）水平抑制小鼠脾虚型肠道腺瘤生长的作用。方法 取70只4周龄的雄性C57BL/6J小鼠,采用对氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导小鼠结直肠腺瘤模型,将建模小鼠随机分为模型组、阿司匹林（200 mg·kg^-1）组、miR inhibitor-NC （2 mg·kg^-1）组、miR-205-5p inhibitor （2 mg·kg^-1）组和三子颗粒低、中、高剂量（1.7、3.4、6.8 g·kg^-1）组,造模期间ig给药,每天1次。比较各组小鼠肠道腺瘤的数量并测量腺瘤体积;苏木素-伊红（HE）染色观察小鼠肠道腺瘤的病理情况;CCK-8法检测各组小鼠肠道腺瘤细胞增殖活力;原位末端标记（TUNEL）法检测小鼠肠道腺瘤细胞凋亡;实时荧光定量PCR（qRT-PCR）法检测肠道腺瘤miR-205-5p表达量及磷酸酯酶与张力蛋白同源物（PTEN）、B淋巴细胞瘤-2（Bcl-2）、Bcl-2相关X蛋白（Bax）、Ki67 mRNA表达量;Western blotting法检测PTEN、Bcl-2、Bax、Ki67蛋白表达水平;荧光素酶活性实验验证miR-205-5p和PTEN的靶向关系。结果 与模型组比较,阿司匹林组和三子颗粒低、中、高剂量组小鼠肠道腺瘤数量、体积及细胞增殖活性均显著降低,凋亡率显著升高（P＜0.05）,miR-205-5p表达量、Bcl-2、Ki67 mRNA及蛋白表达量显著降低,PTEN、Bax mRNA及蛋白表达量显著升高（P＜0.05）,其中三子颗粒作用呈剂量相关性;与miR inhibitor-NC组比较,miR-205-5p inhibitor组小鼠肠道腺瘤数量、体积及细胞增殖活性均显著降低,凋亡率显著升高（P＜0.05）,miR-205-5p表达量、Bcl-2、Ki67 mRNA及蛋白表达量显著降低,PTEN、Bax mRNA及蛋白表达量显著升高（P＜0.05）;荧光素酶活性实验证实miR-205-5p可靶向调控PTEN。结论 三子颗粒可抑制小鼠脾虚型肠道腺瘤生长,可能是通过下调miR-205-5p,上调PTEN、Bax表达,下调Bcl-2、Ki67表达发挥作用的。     

Monoterpene glycoside and flavonoids from <Emphasis Type="Italic">Blumea lacera</Emphasis>

The dichloromethane extract of air-dried leaves of Blumea lacera (Asteraceae) afforded α-pinene-7β-O-β-d-2,6-diacetylglucopyranoside (1), 5,4′-dihydroxy-6,7,3′-trimethoxyflavone (2), and 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone (3). Compounds 1–3 showed moderate activity against Candida albicans, low activity against Trichophyton mentagrophytes, and were inactive against Aspergillus niger. Compounds 1 and 3 indicated low activity against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and were inactive against Bacillus subtilis, while 2 was inactive against all four bacteria tested.     

Anti-acne activities of pulsaquinone, hydropulsaquinone, and structurally related 1, 4-quinone derivatives

Quinone type compound, pulsaquinone 1, isolated from the aqueous ethanol extract of the roots of Pulsatilla koreana exhibited antimicrobial activities against an anaerobic non-spore-forming gram-positive bacillus, Propionibacterium acnes, which is related with the pathogenesis of the inflamed lesions in a common skin disease, acne vulgaris. Compound 1 was unstable on standing and thus converted to more stable compound 2, namely hydropulsaquinone by hydrogenation, whose activity was comparable to mother compound 1 (MIC for 1 and 2 against P. acnes: 2.0 and 4.0 μg/mL, respectively). Other structurally-related quinone derivatives (3–13) were also tested for structure-activity relationship against anaerobic and aerobic bacteria, and fungi. The antimicrobial activity was fairly good when the quinone moiety was fused with a nonpolar 6- or 7-membered ring on the right side whether or not conjugated (1,4-naphtoquinone derivatives 3–5), while simple quinone compounds 6–9 showed poor activity. It seems that the methoxy groups at the left side of the quinone function deliver no considerable antimicrobial effect.     

灰树花多糖体外抑菌及抗氧化活性研究

目的 研究灰树花多糖的抑菌及抗氧化活性。方法 采用紫外分光光度法,以D-无水葡萄糖为对照品,测定灰树花提取物中多糖含量;采用纸片扩散法,以头孢哌酮为阳性对照,测量不同浓度灰树花多糖提取物金黄色葡萄球菌、大肠杆菌、枯草芽孢杆菌的抑菌圈直径;采用DPPH法和T-AOC试剂盒法,以清除率为指标,研究灰树花多糖的抗氧化活性。结果 灰树花提取物中多糖含量为53.49%;灰树花提取物对金黄色葡萄球菌、大肠杆菌、枯草芽孢杆菌均有一定的抑菌作用,抑菌圈直径分别为13,11,10 mm;灰树花多糖浓度为0.05~10 mg·mL^-1时,对DPPH自由基具有一定的清除能力,当浓度高于0.5 mg·mL^-1时,开始显示出总抗氧化能力。结论 灰树花多糖具有一定的抑菌和抗氧化能力。     

New isoflavones from Belamcandae Rhizoma

Four new isoflavones (iristectrigenin A-7-glucoside (2), 8-hydroxytectrigenin (5), 8-hydroxyiristectrigenin A (6), and 8-hydroxyirigenin (7–1) have been isolated from Belamcandae Rhizoma (the rhizome of Belamcanda chinensis), along with nine known compounds: tectridin (1), tectrigenin-4′-glucoside (3), astragalin (4), irilin D (7–2), isotectrigenin (8), tectrigenin (9), iristectrigenin B (10), hispiludin (11–1), and irigenin (11–2). The structures of 2, 5, 6 and 7–1 were determined by spectroscopic methods, including high-resolution mass spectrometry (HR-MS), proton nuclear magnetic resonance (¹H-NMR), carbon-13 NMR (¹³C-NMR), and various two-dimensional (2D)-NMR techniques.     

Bile acid derivatives from a sponge-associated bacterium Psychrobacter sp.

In our search for bioactive metabolites from a marine sponge-associated bacterium Psychrobacter sp., a new bile acid derivative (1), which was assumed to be an artifact, were isolated along with six known (2–7) compounds by bioactivity-guided fractionation. Elucidation of the structure of the new compound was done using a combination of NMR (¹H, ¹³C, HMBC, HSQC, and COSY) and MS spectroscopy. Compound 1 exhibited moderate suppressive effects on both NO and IL-6 production at a concentration of 200 μM (87.3 μg/mL) without significant cytotoxicity against cells. Compounds 2–5 and 7 showed selective inhibitory activity against several human pathogenic bacterial strains at the low concentration of 30 μg/well. In a cytotoxicity evaluation, only compound 7 showed mild cytotoxicity against five human solid tumor cell lines (A-549, SK-OV-3, SK-MEL-2, XF-498, and HCT-15) with ED₅₀ values in the range of 11–14 μg/mL. These authors equally contributed to this work     

Triterpenoic acids of Prunella vulgaris var. lilacina and their cytotoxic activities In Vitro

The column chromatographic separation of the MeOH extract from the aerial parts of Prunella vulgaris var. lilacina Nakai led to the isolation of fifteen triterpenoic acids (2–6, 9–13, 16–20), four flavonoids (14, 21–23), four phenolics (7, 8, 15, 24), and a diterpene (1). Their structures were determined by spectroscopic methods to be trans-phytol (1), oleanic acid (2) ursolic acid (3), 2α,3α,19α-trihydroxyurs-12en-28oic acid (4), 2α,3α-dihydroxyurs-12en-28oic acid (5), maslinic acid (6), caffeic acid (7), phydroxy cinnamic acid (8), 2α,3α,19α,23-tetrahydroxyurs-12en-28oic acid (9), 2α,3α,23-trihydroxyurs-12en-28oic acid (10), 2α,3β-dihydroxyurs-12en-28oic acid (11), 2α,3β,24-trihydroxyolea-12en-28oic acid (12), (12R, 13S)-2α,3α,24,trihydroxy-12,13-cyclo-taraxer-14-en-28oic acid (13), quercertin 3-O-β-D-glucopyranoside (14), rosmarinic acid (15), 2α,3α,24-trihydroxyurs-12,20(30)-dien-28oic acid (16), 2α,3α,24-trihydroxyolea-12en-28oic acid (17), 2α,3β,19α,24-tetrahydroxyurs-12en-28oic acid 28-O-Dglucopyranoside (18), 2α,3α,19α,24-tetrahydroxyurs-12en-28oic acid 28-O-D-glucopyranoside (19), prunvuloside A (20), kaempferol 3-O-α-L-rhamnopyranosyl(1→6)-β-D-glucopranoside (21), kaempferol 3-O-β-D-glucopyranoside (22), quercertin 3-O-α-L-rhamnopyranosyl(1→6)-β-D-glucopyranoside (23), and 2-hydroxy-3-(3’,4’-dihydroxyphenly)propanoic acid (24). Compounds 1, 8–12, 17, 21, 23, and 24 were isolated from this plant source for the first time. The isolated compounds were evaluated for their cytotoxicity against A549, SK-OV-3, SK-MEL-2, and HCT15 cells in vitro using the sulforhodamin B bioassay (SRB) method. Compound 3 exhibited moderate cytotoxic activity against A549, SK-OV-3, SK-MEL-2, and HCT15 cells, with ED₅₀ values of 3.71, 3.65, 13.62, and 5.44 μM, respectively.     

Synthesis and preliminary evaluation of 2-substituted-1,3-benzoxazole and 3-[(3-substituted)propyl]-1,3-benzoxazol-2(3H)-one derivatives as potent anticancer agents

The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazole and benzoxazolone derivatives are described. The 2-cyclic amine-1,3-benzoxazoles 5a–k, 5-chloro-3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one 8 and 3-[3-(cyclic amino)propyl]-1,3-benzoxazol-2(3H)-ones 9a–f were synthesized. The newly synthesized compounds with the influence of the presence of cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to their cytotoxic effect toward four human cancer cell lines. The new compounds were evaluated to see whether substitution at the second and third position of the benzoxazole motif influence their cytotoxic effect toward cancer cells.     

Nontraditional approaches to the synthesis of some biologically active substituted <Emphasis Type="Italic">p</Emphasis>-benzoquinones

The condensation of mono o- or p-substituted anilines (1) with tetrachloro-1,4-benzoquinone (2) has been achieved by using K₂CO₃ under conventional heating, solid solvent-free grinding, solid-phase microwave irradiation (MWI) conditions to obtain substituted dichloro-p-benzoquinone derivatives (3). All the nontraditional methods described herein provide several advantages over prior methods such as higher yield, convenient work-up procedure, and enviro-economic synthesis. It is observed that solid-supported reaction under MWI is the most appropriate for the synthesis of the title compounds. All the synthesized compounds were tested for their in vitro antibacterial and antifungal activity. Some compounds showed promising antimicrobial properties. The best activity was observed with compounds 3b and 3f. Presented at the International Symposium on Current Trends in Drug Discovery Research (CTDDR) (P-12) 17–21 February 2007, Central Drug Research Institute, Luknow, India. (Abstract Published in Medicinal Chemistry Research 2007, 15(1/6):117–118).     

Two new neolignan glycosides from leaves of <Emphasis Type="Italic">Osmanthus heterophyllus</Emphasis>

Two new neolignan glycosides, (7R, 8R)-threo-guaiacylglycerol-8-O-4′-sinapyl ether 7-O-β-d-glucopyranoside (1) and (7S, 8R)-5-methoxydehydrodiconiferyl alcohol 4-O-β-d-glucopyranoside (2), and four known ones (3–6), were isolated from the leaves of Osmanthus heterophyllus. The structures of compounds 1–6 were established on the basis of spectral and chemical data.     

Polyphenolic compounds isolated from the leaves of Myrtus communis

Four hydrolyzable tannins [oenothein B (1), eugeniflorin D₂ (2), and tellimagrandins I (3) and II (4)], two related polyphenolic compounds [gallic acid (5) and quinic acid 3,5-di-O-gallate (6)], and four myricetin glycosides [myricetins 3-O-β-d-xyloside (7), 3-O-β-d-galactoside (8), 3-O-β-d-galactoside 6″-O-gallate (9), and 3-O-α-l-rhamnoside (10)] were isolated from the leaves of Myrtus communis. Antioxidant activities of the isolated compounds were evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay.     

Synthesis and antibacterial activity of N-[5-chlorobenzylthio-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives

A series ofN-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives (4a-1) have been synthesized by reaction of piperazinyl quinolones with 5-chloro-2-(chloroben-zylthio)-1,3,4-thiadiazoles. Their structures were confirmed by elemental analysis, IR and NMR spectra. The antibacterial activities of4a-1 against a variety of Gram-positive and Gram-negative bacteria were determined. Several compounds showed a good antibacterial activity against Gram-positive bacteria among which, compound 4e with a 2-chlorobenzylthio moiety in ciprofloxacin derivative, exhibited high activities againstStaphylococcus aureus andStaphylococcus epidermidis (MIC=0.06 μg/mL). The structure-activity relationship (SAR) study revealed that the position of chlorine atom on benzyl moiety would dramatically affect the antibacterial activities of the synthesized compounds.     

Synthesis and in vitro anti-Helicobacter pylori activity of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles

A new series of 2-[(chlorobenzyl)thio]-5-(5-nitro-2-furyl)-1,3,4-thiadiazoles (6a–h) were synthesized and evaluated by the disc diffusion method against Helicobacter pylori. Four compounds which exhibited strong anti-H. pylori activity at concentration of 8–32 μg/disc (average of inhibition zone >20 mm) were further tested against 20 clinical isolates of H. pylori at lower concentrations. The averages of inhibition zone diameters indicated that all selected compounds exhibit better anti-H. pylori activity profile against clinical isolates of H. pylori with respect to standard drug metronidazole. Compound 6c, containing the 3-chlorobenzylthio moiety, was the most potent compound tested.