Estimation of the efficacy of screened natural hypolipidemic compounds in a model of rabbit hypercholesterolemia]

Thirteen strains producing hydrophobic compounds with high hypolipidemic activity were screened among 657 tested strains of fungi, actinomycetes and bacteria with the use of 2 models. The further aim of the study was to estimate the efficacy of the compounds with respect to their ability to inhibit cholesterol synthesis in vivo. For that purpose a model of hyperlipidemia in rabbits was used. The model provided screening of 9 new compounds that showed satisfactory hypolipidemic effect evident from a significant decrease of the lipid levels in the rabbit serum. The study of the serum lipid profile revealed that the inhibitory effect of compounds No. 16 and No. 281 was similar to that of lovastatin whereas the serum level of general cholesterol remained decreased for a longer period. Compound No. 25 was of interest because of its possible use in low doses and significant effect on the serum triglyceride fraction.     

Screening of natural immunosuppressors by their ability to modify steroid synthesis in hepatocytes]

In the programme for screening sterol synthesis inhibitors with the use of actinomycetes and fungi 702 strains were tested. The effect of alcohol extracts of the mycelium of fungi and actinomycetes at a dilution of 1/10(3) on sterol synthesis by the Hep G2 hepatome cells was determined by incorporation of 3H acetate into sterols and proteins. Lovastatin (200 pg/ml) was used as the control: the sterol synthesis was decreased by 49 +/- 4% without inhibiting the protein synthesis. A number of the cultures produced compounds inhibiting under the experimental conditions the synthesis of sterols by 70 to 80% with simultaneous inhibition of the protein synthesis at least by 60 to 70%. Three compounds from that group produced by streptomycetes were subjected to a more detailed investigation. The compounds were demonstrated to be active antifungal antibiotics (MIC 0.1-1 mcg/ml). In a dose of 0.1-1 mcg/ml they showed high immunosuppressive activity in models of lymphocyte transformation in mice, whereas cyclosporin was active in a dose of 1 mcg/ml. Therefore, the model for screening hypolipidemic compounds could be considered useful for screening promising natural immunosuppressors.     

Effect of novel natural hypolipidemic compounds on human immunodeficiency virus]

Target screening among microbial products resulted in isolation of hypolipidemic compounds tested for activity against HIV in culture of transferable lymphoblastoid cells MT-4. The majority of the compounds showed antiviral activity. The highest antiviral effect was observed when before exposure to the virus the cells were preincubated for 1 hour in the presence of the isolated compounds. The compounds showed no effect when added to the cell culture preliminarily infected by HIV.     

Syntheses and Biological Evaluation of Alkanediamines as Antioxidant and Hypolipidemic Agents

A new series of compounds belonging to N,N′- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2–5a–f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity.     

Contribution to investigation of antimicrobial activity of styrylquinolines

Series of new ring-substituted styrylquinolines and two oxorhenium complexes were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against fungal and bacterial strains. Some compounds were active against bacteria at micromolar level and against fungi at submicromolar level. Compounds 5,7-dichloro-2-[2-(2-ethoxyphenyl)vinyl]quinolin-8-ol expressed excellent antifungal activity comparable with or higher than the standard fluconazole as well as antibacterial activity against Staphylococcus strains comparable with or higher than the standards bacitracin, penicillin and ciprofloxacin. The structure–activity relationships are discussed.     

Trypanosoma brucei gambiense: growth in vitro of bloodstream forms inhibited by dichlorodiammineplatinum (II) compounds and hypolipidemic drugs

Infectious bloodstream forms of Trypanosoma brucei gambiense were grown in microcultures of murine bone marrow cells in 96-well tissue culture plates. Limiting dilution studies showed that fewer than 10 cultured trypanosomes developed into populations of about 5 X 10(4) parasites per well in a week. Bloodstream parasites were reisolated with high efficiency from mice infected with cultured parasites; fewer than 10 bloodstream parasites successfully established a trypanosome population in a microculture. Both the cis and trans isomers of dichlorodiammineplatinum (II) (cisplatin and transplatin) and a hypolipidemic agent, Wy 14643, were found to have activity against T. b. gambiense growing in microcultures. The minimum concentration of drug necessary to completely eliminate parasites from microcultures was 4 microM for cisplatin, 40 microM for transplatin, and 500 microM for Wy 14643. A preformed complex of cisplatin and bovine serum albumin and another hypolipidemic agent, chlofibric acid, were inactive. This culture system should be useful for rapid screening of large numbers of compounds for trypanocidal activity.     

连翘和水茄内生放线菌的多样性、活性及生物合成基因的PCR筛查

从采自成都地区的中药植物连翘Forsythia suspense和水茄Solanum torvum的根部分离到14株内生放线菌。活性筛选表明,10株菌的发酵粗提物具有不同程度的抗肿瘤活性,占全部菌株的71%;3株菌具有抗细菌活性,其中菌株A263具有较强的细胞毒活性和广谱抗细菌活性。基于16S rRNA基因部分序列的相似性分析表明,菌株A275属于克里贝拉菌属Kribbella,其余13株属于链霉菌属Streptomyces。多种生物合成基因的筛查实验表明,5株菌同时具有PKS-I、PKS-II、NRPS型基因,其中A255和A263还具有3,5-AHBA合酶基因,但仅A275具有oxyB基因。结果可以推测,链霉菌是这2种中药植物根部的优势内生放线菌,生物合成基因的PCR筛查能极大地弥补传统活性筛选模型的不足,内生放线菌具有产生丰富生物活性化合物的巨大潜力。     

Thermal solvent-free synthesis of chromonyl chalcones, pyrazolines and their in vitro antibacterial, antifungal activities

A facile and ecofriendly synthesis of new chromonyl chalcones 3a-b from 3-formylchromone 1 and active methyl compounds 2a-b is reported under thermal solvent-free heating condition in good yields. The chromonyl chalcones 3a-b were used as intermediates under green condition for the synthesis of new bioactive pyrazoline derivatives 4a-f. The compounds were tested for antimicrobial activity by disk diffusion assay with slight modifications against Gram-positive, Gram-negative strains of bacteria as well as fungal strains. The investigation of antimicrobial screening revealed that compounds 3a-b and 4a-f showed antibacterial and antifungal activities.     

Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents

A new series of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones (4-12a-e) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds, namely 5b, 5d, 6e, 8a, 8b, 10b and 11a, exhibit better antioxidant activity than probucol. Two compounds, 5d and 10b, have been evaluated in detail for antioxidant and hypolipidemic activities and show comparable activity profile to that of probucol and guggulipid. From the present study it may be postulated that the mechanism of action of these compounds could be through activation of lecithin cholesterol acyltransferase (LCAT), liver lipolytic activity, increased faecal bile acid secretion and inhibition of hepatic cholesterol biosynthesis.     

Antibacterial, antifungal and cytotoxic activity of terrestrial cyanobacterial strains from Serbia

Cyanobacteria are known to be a rich source of biologically active compounds some of which can have pharmaceutical importance. In this work we present the screening results of cyanobacterial strains for their antibacterial, antifungal, and cytotoxic activity. Cyanobacterial strains were isolated from various soil types in province of Vojvodina and Central Serbia, Republic of Serbia. The screening included 9 strains of Anabaena and 9 strains of Nostoc. Both, extracellular products (from the culture liquid) and cellular crude lipophilic extracts were tested against 13 bacterial strains and 8 fungal strains. Cytotoxic activity was tested against three human cell lines. Methanol extracts were prepared according to ?stensvik. Antibacterial and antifungal activities were determined measuring inhibition zone, 48 h after inoculation. The cytotoxic activity was determined by sulforhodamine B (SRB) colorimetric assay. Of all cyanobacterial strains tested, 52% showed some antifungal and 41% antibacterial activity. Two out of six tested strains possessed cytotoxic activity. The cytotoxic activity of Anabaena strain S12 was found both in culture liquid and crude cell extract. It occurred specifically between the 21st and 42nd day of cultivation against HeLa and MCF7 cells, but had no activity against cell line derived from a healthy tissue. A high percentage of the active strains among the tested strains justify the effort of screening cyanobacteria that are isolated from terrestrial environments. The most promising strains for the fur- ther study are Anabaena strain S12 which showed strong cytotoxic and antibacterial activity and Ana- baena strain S20 which produces a potent antifungal compound. The future work, besides further screening and chemical identification of the active compounds, should also include the development of culture techniques that would lead to more efficient production of biologically active compounds.     

Antimicrobial activity of some new of 2-(4-ethyl-phenoximethyl) benzoic acid thioureides against planktonic cells

The aim of the present study was to evaluate the antimicrobial activity of new 2-(4-ethyl-phenoxymethyl) benzoic acid thioureides. The synthesis of the new compounds was done in three steps starting with the synthesis of 2-(4-ethyl-phenoxymethyl) benzoic acid. In the second stage, the 2-(4-ethyl-phenoxymethyl)-benzoyl chloride was prepared and the new thioureides were synthesized in the third step by the reaction of 2-(4-ethyl-phenoxymethyl) benzoyl isothiocyanate with various primary aromatic amines. The original compounds were screened for their in vitro antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) as well as to fungal strains (Candida albicans, Aspergillus niger), using both reference and clinical, multidrug resistant strains. The qualitative screening of the susceptibility spectra of various microbial strains versus these compounds was performed by three adaptated diffusion methods: (1) impregnation of the filter paper disks with the respective substance solutions, (2) distribution of the tested solutions into agar wells and (3) spotting of the respective solutions on the solid medium previously inoculated with the microbial suspensions. The quantitative assay of the antimicrobial activity was performed by broth microdilution method in 96-well microplates in order to establish the minimal inhibitory concentration (MIC). The tested compounds exhibited specific antimicrobial activity with MICs ranging from 3.9 microg/mL to 250 microg/mL.     

Synthesis and biological evaluation of isoflavone fatty acid esters with potential weight loss and hypolipidemic activities

A series of isoflavone fatty acid esters were designed on the basis of endogenous oleoyl-estrone using estrogen moiety modification strategy. Ten new compounds were synthesized, and their body weight loss and hypolipidemic bioactivities were assayed. Some of these novel compounds could effectively inhibit the differentiation of 3T3-L1 preadipocytes in vitro. The most potent compound 1a significantly decreased the body weight and white adipose tissue weight in a high-fat diet-induced rat model. Also, compound 1a showed good hypolipidemic activity and low toxicity.     

Response of genetically obese Zucker rats to ciprofibrate,a hypolipidemic agent,with peroxisome proliferation activity as compared to Zucker lean and Sprague-Dawley rats

Summary— Genetically obese Zucker (fa/fa) rats were used as an experimental model to study the effects of hypolipidemic agents on peroxisome proliferation; comparison was made with Zucker lean phenotype (Fa/?) and Sprague-Dawley strain/phenotype. The pharmacokinetics of a single administration of ciprofibrate (1 or 3 mg/kg), appeared to be similar in all strains/phenotypes. After a 2-week oral administration at the same dosages, there were dosage-related increases in hepatocellular peroxisomal yield and in the hepatic enzymes' cyanide-insensitive acyl-CoA oxidase and catalase. The peroxisomal yield was less increased in Zucker than in Sprague-Dawley rats, while the enzyme activities were similarly increased. Although the absolute specific activity of microsomal ω-lauryl hydroxylase (cytochrome P4504A1) was lower in Zucker rats, it was increased more in this strain than in Sprague-Dawley rats in response to drug exposure. The hypolipidemic effect (cholesterol and triglyceride reduction) was more pronounced in Zucker obese rats. Based on biochemical and morphological results, no major differences between strains/phenotypes in terms of peroxisome proliferation were observed following a 2-week administration of ciprofibrate.     

Screening of Marine Bacteria for the Production of Microbial Repellents Using a Spectrophotometric Chemotaxis Assay

A method for screening marine bacteria for the production of microbial repellents has been developed. The spectrophotometer provided quantitative information on bacterial chemotaxis in response to extracts from other strains of marine bacteria. Aqueous extracts were incorporated into an agar plug at the base of a cuvette, which was overlaid with a suspension of a motile strain. Negative chemotaxis of the motile strain in response to diffusion of repellent compounds from the agar could be measured by a fall in the optical density, allowing the direct screening of supernatants for repellent activity. Three strains producing metabolites with a repellent effect on a motile marine bacterium were identified. Antibiotic activity and the repellent effect of the supernatants were compared, with no significant correlation being found. The screening method will therefore allow the identification of bioactive metabolites that would be overlooked using traditional antibiotic screening strategies. Received March 4, 1998; accepted November 11, 1998.     

Antifungal Activity of Ring Poly-Chlorinated Pyrimidines: Structure Activity Relationships

A total of 48 ring chlorinated pyrimidines was screened against strains of five fungi by the disc-plate method, in liquid culture, and for activity of the vapors of the compounds. Correlations of the results obtained by the three methods were made, and structure to activity relationships were discussed. The outstanding members of this series were found to be 2,4,5-trichloropyrimidine, 4,5,6-trichloropyrimidine, and 2-chloromethyl-4,5,6-trichloropyrimidine, in this screening system.     

Design, synthesis, and structure-activity relationship studies of new phenolic DNA gyrase inhibitors

Starting from a biased needle screening hit 3a, we report herein the design and synthesis of a series of novel 2,3-dihydroisoindol-1-ones structurally related to cyclothialidine 2 with DNA gyrase inhibitory activity. In this series, some compounds exhibited promising antibacterial activity against gram-positive bacterial strains.     

A novel class of selective anti-Helicobacter pylori agents 2-oxo-2H-chromene-3-carboxamide derivatives

A novel class of selective anti-Helicobacter pylori agents, 2-oxo-2H-chromene-3-carboxamide derivatives, were prepared and evaluated for their anti-bacterial activity. All synthesized compounds showed little or no activity against different species of Gram-positive and Gram-negative bacteria and against various strains of pathogenic fungi. Some of them exhibited a potent and specific inhibitory effect on the growth of H. pylori, including metronidazole-resistant strains, in the 0.0039-16 microg/mL MIC range. A cytotoxic screening by the Trypan blue dye exclusion assay was also carried out on the most active compounds as anti-H. pylori agents. Among the derivatives examined for their cytotoxic potential, a number of them induced low cytotoxic effects.     

Preliminary evaluation of antimicrobial activity of diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocoumarin-4-carboxylic acids

Preliminary differentiating screening of the antibacterial and antifungal activity of a series of diastereomeric cis/trans-3-aryl(heteroaryl)-3,4-dihydroisocoumarin-4-carboxylic acids (3a-i) was performed by the agar diffusion method against twelve microorganism strains of different taxonomic groups. S. aureus and A. niger were the most sensitive strains to the antibiotic effect of the tested compounds, both inhibited by 10 of 12 compounds. The most potent antibacterial agent was cis-3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acid (cis-3a), exhibiting activity against all seven bacterial test strains.     

Actinomycetes from Moroccan habitats: isolation and screening for cytotoxic activities

In our screening for actinomycetes showing cytotoxic activities, 8 samples were collected from various Moroccan habitats, 136 isolates were tested for their capacity to produce antibacterial compounds against gram positive bacteria. Thirty-seven strains of these isolates were active against Gram-positive bacteria. Using the following steps of primary screening: antibacterial activity, confrontation between the isolates and toxicity to Artemia salina; fifteen different isolates were used for further investigation. The aqueous extracts of Streptomyces sp. T5 and Streptomyces sp. AS8 were selected for their cytotoxic activity against Hep2, BSR and P815 cell lines, and two active compounds were observed on HPLC. The two isolates exhibited high activity against human cancer cell lines and were inactive on PBMC cell lines. Furthermore, the Streptomyces sp. T5 extract showed a proliferative activity.     

Discovery of novel benzoquinazolinones and thiazoloimidazoles, inhibitors of influenza H5N1 and H1N1 viruses, from a cell-based high-throughput screen

A highly reproducible and robust cell-based high-throughput screening (HTS) assay was adapted for screening of small molecules for antiviral activity against influenza virus strain A/Vietnam/1203/2004 (H5N1). The NIH Molecular Libraries Small Molecule Repository (MLSMR) Molecular Libraries Screening Centers Network (MLSCN) 100,000-compound library was screened at 50 μM. The "hit" rate (>25% inhibition of the viral cytopathic effect) from the single-dose screen was 0.32%. The hits were evaluated for their antiviral activity, cell toxicity, and selectivity in dose-response experiments. The screen yielded 5 active compounds (SI value >3). One compound showed an SI(50) value of greater than 3, 3 compounds had SI values ranging from greater than 14 to 34, and the most active compound displayed an SI value of 94. The active compounds represent 2 different classes of molecules, benzoquinazolinones and thiazoloimidazoles, which have not been previously identified as having antiviral/anti-influenza activity. These molecules were also effective against influenza A/California/04/2009 virus (H1N1) and other H1N1 and H5N1 virus strains in vitro but not H3N2 strains. Real-time qRT-PCR results reveal that these chemotypes significantly reduced M1 RNA levels as compared to the no-drug influenza-infected Madin Darby canine kidney cells.