共查询到20条相似文献,搜索用时 15 毫秒
1.
Nicholas Stock Christopher Baccei Gretchen Bain Charles Chapman Lucia Correa Janice Darlington Christopher King Catherine Lee Daniel S. Lorrain Pat Prodanovich Angelina Santini Kevin Schaab Jilly F. Evans John H. Hutchinson Peppi Prasit 《Bioorganic & medicinal chemistry letters》2010,20(15):4598-4601
AM643 (compound 6, 3-{3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid) was identified as a potential candidate for formulation as a topical agent for the treatment of skin disorders involving leukotriene production. Dermal application of 6 using a prototypical vehicle in a murine ear arachidonic acid model showed significant reduction in the concentrations of leukotrienes in mouse skin with concomitant reduction in ear swelling. 相似文献
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3.
Zong-Ping Zheng Jinyu Ma Ka-Wing Cheng Jianfei Chao Qin Zhu Raymond Chuen-Chung Chang Ming Zhao Zhi-Xiu Lin Mingfu Wang 《Phytochemistry》2010,71(17-18):2046-2051
Two sulfur-containing compounds, (S)-2-amino-5-((R)-1-carboxy-2-((E)-3-(4-hydroxy-3-methoxyphenyl)allylthio)ethyl-amino)-5-oxopentanoic acid (1) and (S)-2-amino-5-((R)-1-(carboxymethylamino)-3-((E)-3-(4-hydroxyphenyl)allylthio)-1-oxopropan-2-ylamino)-5-oxopentanoic acid (2), and one 1H-pyrrole-2-carboxylic acid derivative, 6-(3-(1H-pyrrole-2-carbonyloxy)-2-hydroxypropoxy)-3,4,5-trihydroxy-tetrahydro-2H-pyran-2-carboxylic acid (3), together with eighteen known phenolic compounds, were isolated from the fruits of pineapple. Their structures were elucidated by a combination of spectroscopic analyses. Some of these compounds showed inhibitory activities against tyrosinase. The half maximal inhibitory concentration values of compounds 1, 4, 5, 6, 7 are lower than 1 mM. These compounds may contribute to the well-known anti-browning effect of pineapple juice and be potential skin whitening agents in cosmetic applications. 相似文献
4.
Trinh Dang Ilyas S. Nizamov Ramazan Z. Salikhov Leysan R. Sabirzyanova Vyacheslav V. Vorobev Tatyana I. Burganova Marina M. Shaidoullina Elvira S. Batyeva Rafael A. Cherkasov Timur I. Abdullin 《Bioorganic & medicinal chemistry》2019,27(1):100-109
The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(–)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(–)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10?µM (6?µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC50?=?48.6 and 57.6?µM, respectively, 72?h), encouraging their further investigation as potential antimicrobials against skin and wound infections. 相似文献
5.
Hernán Pessoa-Mahana Christian González-Lira Angélica Fierro Gerald Zapata-Torres C. David Pessoa-Mahana Javiera Ortiz-Severin Patricio Iturriaga-Vásquez Miguel Reyes-Parada Paul Silva-Matus Claudio Saitz-Barría Ramiro Araya-Maturana 《Bioorganic & medicinal chemistry》2013,21(24):7604-7611
A series of 3-(3-(4-(3-(1H-indol-3-yl)propyl)piperazin-1-yl)propyl)-1H-indole derivatives (3a–d and 5a–f) as homo- and hetero-bis-ligands, were synthesized and evaluated for in vitro affinity at the serotonin transporter (SERT) and the 5-HT1A receptor. Compounds 5b and 5f showed nanomolar affinities for both targets. The experimental data were rationalized according to results obtained from docking experiments. These findings are in agreement with our proposal that bis-indole derivatives can bind both targets, and might serve as leads in the quest of ligands endowed with a dual mechanism of action. 相似文献
6.
Sodium iodide—zinc in N,N-dimethylformamide at 150° converted 2,5-anhydro-3,4-di-O-p-tolylsulfonyl-D-xylose diisobutyl dithioacetal into a mixture of three substituted furans, namely 2-[(isobutylthio)methyl]furan (2), and its 3-isobutylthio- (3), and 4-isobutylthio- (5) derivatives. The relative proportions of 2, 3, and 5, determined by g.l.c.—mass spectrometry, varied according to the relative proportions of reactants employed. A similar type of transposition—elimination is also encountered in the absence of sodium iodide. Compound 3 is also produced from D-xylose disobutyl dithioacetal by extended treatment with 2-methylpropanethiol—hydrochloric acid. The furan derivatives 3 and 5 were characterized mainly by n.m.r.—spectral studies on their Diels—Alder adducts with maleic anhydride, and the mechanism of their formation is discussed. 2,5-Anhydro-3,4-di-O-p-tolylsulfonyl-D-xylose ethylene dithioacetal (13), its ribo epimer (15), and its L-arabino diisobutyl dithioacetal analog (20) all reacted with sodium iodide—zinc in N,N-dimethylformamide exclusively by an E2 type of elimination with formation of the anticipated 3-alkenes, namely 2,5-anhydro-3,4-dideoxy-D-glycero-pent-3-enose ethylene dithioacetal (14) and its diisobutyl dithioacetal analog. 相似文献
7.
Methyl 2-O-benzoyl-3-bromo-3,6-dideoxy-α-l-altropyranoside (4) and methyl 2-O-benzoy]-3-bromo-3,6-dideoxy-4-O-methyl-α-l-altropyranoside (5) have been prepared from methyl-α-l-rhamnopyranoside, respectively, in 2 and 3 steps. Reduction of 4 with lithium aluminium hydride followed by acid hydrolysis afforded the 3,6-dideoxy-l-arabino-bexose (l-ascarylose). The anhydro sugars 8 and 9 have been used as intermediates in the stereoselective synthesis of 6-deoxy-3-O-methyl-l-altropyranose (l-vallarose) and of 3-amino-3-degxy-l-altro sugars. Under azidolysis conditions, and according to the temperature, 5 gave unsaturated sugars such as 20 and the derived 26, or azido compounds such as 21 and 24, and the derived sugar methyl 2-amino-2,3,6-trideoxy-α-l-threo-hexopyranosid-4-ulose (25). 相似文献
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A novel series of coumarin-1,2,4-oxadiazole hybrids were designed, synthesized, and evaluated as anticonvulsant agents. The title compounds were easily synthesized from reaction of appropriate coumarins and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazole derivatives. In vivo anticonvulsant activity of the synthesized compounds were determined using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures confirming that they were more effective against MES test than PTZ test. It should be noted that compounds 3b, 3c, and 3e showed the best activity in MES model which possessed drug-like properties with no neurotoxicity. Anticonvulsant activity of the most potent compound 3b was remarkably reduced after treatment with flumazenil which confirmed the participation of a benzodiazepine mechanism in the anticonvulsant activity. Also, docking study of compound 3b in the BZD-binding site of GABAA receptor confirmed possible binding of 3b to the BZD receptors. 相似文献
9.
Krzysztof Kamiński Jolanta Obniska Iwona Chlebek Beata Wiklik Sabina Rzepka 《Bioorganic & medicinal chemistry》2013,21(21):6821-6830
The synthesis and anticonvulsant properties of new N-Mannich bases of 3-phenyl- (9a–d), 3-(2-chlorophenyl)- (10a–d), 3-(3-chlorophenyl)- (11a–d) and 3-(4-chlorophenyl)-pyrrolidine-2,5-diones (12a–d) were described. The key synthetic strategies involve the formation of 3-substituted pyrrolidine-2,5-diones (5–8), and then aminoalkylation reaction (Mannich-type) with formaldehyde and corresponding secondary amines, which let to obtain the final compounds 9a–d, 10a–d, 11a–d and 12a–d in good yields. Initial anticonvulsant screening was performed in mice (ip) using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The most effective compounds in mice were tested after oral administration in rats. The acute neurological toxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective especially in the MES test (model of human tonic-clonic seizures). The most active in the MES seizures in rats was 1-[(4-benzyl-1-piperidyl)methyl]-3-(2-chlorophenyl)pyrrolidine-2,5-dione (10c) which showed ED50 value of 37.64 mg/kg. It should be stressed that this molecule along with 9a, 9d and 10d showed protection in the psychomotor seizure test (6-Hz), which is known as an animal model of therapy-resistant epilepsy. Furthermore compounds 9a, 9d and 10d were also tested in the pilocarpine-induced status prevention (PISP) test to assess their potential effectiveness in status epilepticus. For the most promising molecule 9d an influence on human CYP3A4 isoform of P-450 cytochrome was studied in vitro. 相似文献
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《Bioorganic & medicinal chemistry》2016,24(21):5521-5533
The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6–10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30–33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays. Although several compounds exhibited marked inhibitory activity at a higher concentration against Mtb, M. bovis, S. aureus and E. faecalis, they displayed unexpected synergistic and additive interactions at their lower concentrations with antitubercular drugs isoniazid and rifampicin, and antibacterial drug gentamicin. The active analogues were also found to inhibit intracellular Mtb in a human monocytic cell line infected with H37Ra. Oral administration of 5-hydroxymethyl-3-N-(2-propynyl)-3′-azido-2′,3′-dideoxyuridine (32) and 5-hydroxymethyl-3-N-(2-propynyl)-2′,3′-dideoxyuridine (33) at a dose of 100 mg/kg for two weeks showed promising in vivo effects in mice infected with Mtb (H37Ra). No in vitro cytotoxicity of the test compounds was observed up to the highest concentration tested (CC50 > 300 μg/mL). 相似文献
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《Bioorganic & medicinal chemistry》2014,22(17):4587-4596
5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2′-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1–8 showed the best binding affinity with a Ki value of 8.69 nM and it was verified as a novel antagonist according to functional assays. The compound 1–8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1–8 exhibited an antidepressant effect at a dose of 25 mg/kg in the forced swimming test in mice and showed a U-shaped dose–response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone. 相似文献
12.
Guozhang Xu Michael D. Gaul Gee-Hong Kuo Fuyong Du June Zhi Xu Nathaniel Wallace Simon Hinke Thomas Kirchner Jose Silva Norman D. Huebert Seunghun Lee William Murray Yin Liang Keith Demarest 《Bioorganic & medicinal chemistry letters》2018,28(21):3446-3453
A new series of (2S,3R,4R,5S,6R)-5-fluoro-6-(hydroxymethyl)-2-aryltetrahydro-2H-pyran-3,4-diols as dual inhibitors of sodium glucose co-transporter proteins (SGLTs) were disclosed. Two methods were developed to efficiently synthesize C5-fluoro-lactones 3 and 4, which are key intermediates to the C5-fluoro-hexose based C-aryl glucosides. Compound 2b demonstrated potent hSGLT1 and hSGLT2 inhibition (IC50?=?43?nM for SGLT1 and IC50?=?9?nM for SGLT2). It showed robust inhibition of blood glucose excursion in oral glucose tolerance test (OGTT) in Sprague Dawley (SD) rats and exerted pronounced antihyperglycemic effects in db/db mice and high-fat diet-fed ZDF rats when dosed orally at 10?mg/kg. 相似文献
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t-Butyl 6-cyano-(3R,5R)-dihydroxyhexanoate ((3R,5R)-2) is an important chiral diol synthon of atorvastatin calcium. Previously, we constructed a variant KmAKR-W297H (M1) of Kluyveromyces marxianus aldo-keto reductase (KmAKR, designated as M0), possessing excellent diastereoselectivity but moderate activity towards t-butyl 6-cyano-(5R)-hydroxy-3-oxohexanoate ((5R)-1). In this work, KmAKR-W297H/Y296W/K29H (M3) was developed via semi-rational design. It exhibited much improved catalytic efficiency towards (5R)-1. The Km values of M3 for NADPH and (5R)-1 were 0.15 mmol/L and 1.41 mmol/L, and the maximal reaction rate vmax was 55.56 μmol/min/mg. Compared with M1, the catalytic efficiency kcat/Km of M3 was increased 2.64-fold. Coupled with Exiguobacterium sibiricum glucose dehydrogenase (EsGDH) for nicotinamide adenine dinucleotide phosphate (NADPH) regeneration, M3 took 3.5 h to completely reduce (5R)-1 at up to 100.0 g/L, producing 237.4 mmol/L (3R,5R)-2 in d.e.P value above 99.5%. The space-time yield (STY) of M3-catalyzed (3R,5R)-2 synthesis was 372.8 g/L/d. 相似文献
14.
《Carbohydrate research》1986,147(2):237-245
The reaction of diglycol- and thiodiglycol-aldehyde (1a,b) with cyanoacetamide yields cis-3,5-diacetoxy-4-carbamoyl-4-cyano-tetrahydropyran (2a) and -tetrahydrothiopyran (2b). When this reaction is applied to (2S)-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1c), (2S)-3,5-dihydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-1,4-dioxane (1d), and (2S,3R,5S)-2-(3-acetyl-2-methyl-5-furyl)-3,5-dihydroxy-1,4-dioxane (1e), 5-(3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2c), 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-methoxycarbonyl-2-methylfuran (2e), and 3-acetyl-5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-2-methylfuran (2f), respectively, are formed with (4S,5S)-4-carbamoyl-4-cyano-2-(3-ethoxycarbonyl-2-methyl-5-furyl)-5-hydroxy-5,6-dihydropyran (3a) and (4S,5S)-4-carbamoyl-4-cyano-5-hydroxy-2-(3-methoxycarbonyl-2-methyl-5-furyl)-5,6-dihydropyran (3b) as minor products. The dehydration of 2a,b, 5-(2,4-di-O-acetyl-3-carbamoyl-3-cyano-3-deoxy-β-d-xylo-pentopyranosyl)-3-ethoxycarbonyl-2-methylfuran (2d), 2e, and 2f yields cis-3,5-diacetoxy-4,4-dicyano-tetrahydropyran and -tetrahydrothiopyran (2l,m), and the 5-(2,4-di-O-acetyl-3,3-dicyano-3-deoxy-β-d-erythro-pentopyranosyl) derivatives (2n–p) of 3-ethoxycarbonyl-2-methylfuran, 3-methoxycarbonyl-2-methylfuran, and 3-acetyl-2-methylfuran, respectively. 相似文献
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Digitalis purpurea normal callus suspension culture is capable of metabolizing 5β-pregnane-3,20-dione (1) to 3β-hydroxy-5β-pregnan-20-one (2), 3α-hydroxy-5β-pregnan-20-one (3), 3β-hydroxy-5β-pregnan-20-one glucoside (7) and 3α-hydroxy-5β-pregnan-20-one glucoside (8). Digitalis purpurea habituated callus suspension culture is also capable of metabolizing 1 to 2, 3, 5β-pregnane-3β,20β-diol (5), (7), (8), 5β-pregnane-3β,20α-diol monoglucoside (9) and 5β-pregnane-3α,20α-diol monoglucoside (11). Furthermore, it was observed that 3β-hydroxy-5β-pregnan-20-one (2) is converted to 7, 9 and 11 by both suspension cultures. At the same time, 1, 3, 5 and 8 were detected in normal callus, while 5β-pregnane-3β,20α-diol (4) and 5β-pregnane-3β,20β-diol monoglucoside (10) were present in the habituated callus culture. 相似文献
16.
Cancer preventive agents. Part 8: Chemopreventive effects of stevioside and related compounds 总被引:1,自引:0,他引:1
Midori Takasaki Takao Konoshima Mutsuo Kozuka Harukuni Tokuda Junko Takayasu Hoyoku Nishino Masazumi Miyakoshi Kenji Mizutani Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》2009,17(2):600-605
In a search for potential cancer chemopreventive agents from natural resources, stevioside (1), a sweetener, and six related compounds, including two aglycones steviol (6) and isosteviol (7), were screened in an in vitro assay for inhibitory effects on Epstein–Barr virus early antigen activation. Compounds 1, 6 and 7 showed significant activity in this assay and also exhibited strong inhibitory effects in a two-stage carcinogenesis test using mouse skin induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of these three compounds were greater than that of glycyrrhizin. Furthermore, these three compounds significantly inhibited mouse skin carcinogenesis initiated by peroxynitrite and promoted by TPA. Their activities were comparable to that of curcumin. These results suggested that 1, as well as 6 and 7, could be valuable as chemopreventive agents for chemical carcinogenesis. 相似文献
17.
《Endocrine practice》2018,24(1):53-59
Objective: It is unclear whether seasonal variations in vitamin D concentrations affect the hypothalamo-pituitary-thyroid axis. We investigated the seasonal variability of vitamin D and serum thyrotropin (TSH) levels and their interrelationship.Methods: Analysis of 401 patients referred with nonspecific symptoms of tiredness who had simultaneous measurements of 25-hydroxyvitamin D3 (25[OH]D3) and thyroid function. Patients were categorized according to the season of blood sampling and their vitamin D status.Results: 25(OH)D3 levels were higher in spring-summer season compared to autumn-winter (47.9 ± 22.2 nmol/L vs. 42.8 ± 21.8 nmol/L; P = .02). Higher median (interquartile range) TSH levels were found in autumn-winter (1.9 [1.2] mU/L vs. 1.8 [1.1] mU/L; P = .10). Across different seasons, 25(OH)D3 levels were observed to be higher in lower quartiles of TSH, and the inverse relationship was maintained uniformly in the higher quartiles of TSH. An independent inverse relationship could be established between 25(OH)D3 levels and TSH by regression analysis across both season groups (autumn-winter: r = -0.0248; P<.00001 and spring-summer: r = -0.0209; P<.00001). We also observed that TSH varied according to 25(OH)D3 status, with higher TSH found in patients with vitamin D insufficiency or deficiency in comparison to patients who had sufficient or optimal levels across different seasons.Conclusion: Our study shows seasonal variability in 25(OH)D3 production and TSH secretion in euthyroid subjects and that an inverse relationship exists between them. Further studies are needed to see if vitamin D replacement would be beneficial in patients with borderline thyroid function abnormalities.Abbreviations: 25(OH)D2 = 25-hydroxyvitamin D2; 25(OH)D3 = 25-hydroxyvitamin D3; AITD = autoimmune thyroid disease; FT4 = free thyroxine; TFT = thyroid function test; TSH = thyrotropin; UVB = ultraviolet B 相似文献
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A series of pyrazolo[3.4,d]thiazole hybrids 6 were synthesized from 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5. The 5-arylidene-2-imino-3-(4-arylthiazol-2-yl)-thiazolidin-4-ones 5 were synthesized from 2-amino-4-arylthiazoles 1 and 2-chloro-acetamido-4-arylthiazoles 2 via the formation of 2-imino-3-(4-substituted-arylthiazol-2-yl)-thiazolidin-4-ones 3 using substituted aldehydes 4. The 5-acrylidene derivative 5 on cyclisation with phenyl hydrazine give the pyrazolo [3, 4, d] thiazole derivatives 6. The obtained pyrazolo [3.4, d]thiazole derivatives were studied as anti-HIV-1 NNRT inhibitors. It was found that these compounds might have potent RT inhibition activity. 相似文献
20.
《Bioorganic & medicinal chemistry》2014,22(5):1690-1699
Oroidin (1), (E)-N-(3-(2-amino-1H-imidazol-4-yl)allyl)-4,5-dibromo-1H-pyrrole-2-carboxamide, is a pyrrole alkaloid isolated from the marine sponge Agelas oroides. Routine screening in a panel of twelve cancer cell lines revealed 1 to be poorly cytotoxic with the 50% growth inhibition concentration (GI50) of 42 μM in MCF-7 (breast) cells and 24 μM in A2780 (ovarian) cells and >50 μM in all other cell lines tested. The development of eight focused libraries comprising thirty compounds total identified N-(biphenyl-4-ylmethyl)-1H-pyrrole-2-carboxamide (4l), N-benzyl-4,5-dibromo-1H-pyrrole-2-carboxamide (5a) and N-(biphenyl-4-ylmethyl)-4,5-dibromo-1H-pyrrole-2-carboxamide (5l) as potent inhibitors of cell growth in our panel of cell lines. Of these compounds GI50 values of <5 μM were observed with 4l against HT29 (colon) and SW480 (colon); 5a against HT29; and 5l against HT29, SW480, MCF-7, A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreas) cell lines. As a cancer class, colon cancer appears to be more sensitive to the oroidin series of compounds, with analogue 5l being the most active. 相似文献