Synthesis and QSAR studies of novel triazole compounds containing thioamide as potential antifungal agents

Eighteen novel triazole compounds containing thioamide were designed and synthesized. Their structures were confirmed by elemental analysis, H-1 NMR, IR, and MS. The title compounds exhibited certain antifungal activity. And the geometry structures of the title compounds were optimized by means of the density functional theory (DFT) method at B3LYP/6-31G* level. The quantitative structure-activity relationship (QSAR) of the title compounds was systematically investigated. A correlative equation between FA and DELH, V was well established by using the multiple linear regression (MLR). (c) 2006 Elsevier Ltd. All rights reserved.

High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections

The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of approximate to 20,000 microbial extracts, 12 hits were identified with broadspectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.

Destruction of Chemical Agents in a Plasma Reactor with Working Gas of Hydrogen

Synthesis of analogues of flazin, in particular, flazinamide, as promising Anti-HIV agents

Flazin isolated from the fruiting bodies of Suillus granulatus was found to possess weak anti-HIV activity (EC50=2.36 mu m, TI= 12.1). To establish a SAR study, 46 flazin analogues were synthesized, and their anti-HIV activities were evaluated in vitro. A

Anti Human Immunodeficiency Virus-1 (HIV-1) Agents 3. Synthesis and in Vitro Anti-HIV-1 Activity of Some N-Arylsulfonylindoles

In order to find compounds with superior anti human immunodeficiency virus type 1 (HIV-1) activity, twelve simple N-arylsulfonylindoles (3a-1) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro for the first time. Several compounds

Anti HIV-1 Agents 2. Discovery of Dibenzofurans as New HIV-1 Inhibitors In Vitro

Ten dibenzofurans were synthesized and evaluated as human immunodeficiency virus (HIV)-1 inhibitors in vitro for the first time. Among these compounds, compounds 1, 6, 7 and 8 demonstrated significant anti-HIV-1 activity. Especially compound 1 showed the

Anti Human Immunodeficiency Virus-1 (HIV-1) Agents 1. Discovery of Benzyl Phenyl Ethers as New HIV-1 Inhibitors in Vitro

Ten single benzyl phenyl ethers were synthesized and evaluated as human immunodeficiency virus-1 (HIV-1) inhibitors in vitro for the first time. Among these compounds, especially 4-nitrobenzyl phenyl ether (3h) exhibited the highest anti-HIV-1 activity wi

Anti Human Immunodeficiency Virus Type 1 (HIV-1) Agents 4. Discovery of 5,5 '-(p-Phenylenebisazo)-8-hydroxyquinoline Sulfonates as New HIV-1 Inhibitors in Vitro

To search for compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, ten 5,5'-(p-phenylenebisazo)-8-hydroxyquinoline sulfonates (4a-j) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro for the first time. Some compounds demonstrated anti-HIV-1 activity, especially 5,5'-(p-phenylenebisazo)-8-hydroxyquinoline p-ethylbenzenesulfonate (4g) and 5,5'-(p-phenylenebisazo)-8-hydroxyquinoline p-chlorobenzenesulfonate (41) showed the more potent anti-HIV-1 activity with 50% effective concentration (EC50) values of 2.59 and 4.01 mu g/ml, and therapeutic index (TI) values of 31.77 and 24.51, respectively.

Anti HIV-1 agents 5: Synthesis and anti-HIV-1 activity of some N-arylsulfonyl-3-acetylindoles in vitro

In continuation of our program aimed at the discovery and development of compounds with superior anti-human immunodeficiency virus type 1 (HIV-1) activity, 21N-arylsulfonyl-3-acetylindole analogs (2a-u) were synthesized and preliminarily evaluated as HIV-1 inhibitors in vitro. Among of all the analogs, several compounds exhibited significant anti-HIV-1 activity, especially N-phenylsulfonyl-3-acetyl-6-methylindole (2j) and N-(p-ethyl)phenylsulfonyl-3-acetyl-6-methylindole (2n) showed the most potent anti-HIV-1 activity with EC50 values of 0.36 and 0.13 mu g/mL, and TI values of >555.55 and 791.85, respectively. It demonstrated that introduction of the acetyl group at the 3-position of N-arylsulfonyl-6-methylindoles could generally lead to the more potent analogs. (C) 2010 Elsevier Ltd. All rights reserved.

Effects of adrenergic agents on the expression of zebrafish (Danio rerio) vitellogenin Ao1

Teleost vitellogenins (VTGs) are large multidomain apolipoproteins, traditionally considered to be estrogen-responsive precursors of the major egg yolk proteins, expressed and synthesized mainly in hepatic tissue. The inducibility of VTGs has made them one of the most frequently used in vivo and in vitro biomarkers of exposure to estrogen-active substances. A significant level of zebrafish vtgAo1, a major estrogen responsive form, has been unexpectedly found in heart tissue in our present studies. Our studies on zebrafish cardiomyopathy, caused by adrenergic agonist treatment, suggest a similar protective function of the cardiac expressed vtgAo1. We hypothesize that its function is to unload surplus intracellular lipids in cardiomyocytes for "reverse triglyceride transportation" similar to that found in lipid transport proteins in mammals. Our results also demonstrated that zebrafish vtgAo1 mRNA expression in heart can be suppressed by both (x-adrenergic agonist, phenylephrine (PE) and beta-adrenergic agonist, isoproterenol (ISO). Furthermore, the strong stimulation of zebrafish vtgAo1 expression in plasma induced by the beta-adrenergic antagonist, MOXIsylyl, was detected by Enzyme-Linked ImmunoSorbent Assay (ELISA). Such stimulation cannot be suppressed by taMOXIfen, an antagonist to estrogen receptors. Thus, Our present data indicate that the production of teleost VTG in vivo can be regulated not only by estrogenic agents, but by adrenergic signals as well. (c) 2009 Elsevier Inc. All rights reserved.

Deletion of yeast CWP genes enhances cell permeability to genotoxic agents

We have previously reported the development of a novel genotoxic testing system based on the transcriptional response of the yeast RNR3-lacZ reporter gene to DNA damage. This system appears to be more sensitive than other similar tests in microorganisms, and is comparable with the Ames test. In an effort to further enhance detection sensitivity, we examined the effects of altering major cell wall components on cell permeability and subsequent RNR3-lacZ sensitivity to genotoxic agents. Although inactivation of single CWP genes encoding cell wall mannoproteins had little effect, the simultaneous inactivation of both CWP1 and CWP2 had profound effects on the cell wall structure and permeability. Consequently, the RNR3-lacZ detection sensitivity is markedly enhanced, especially to high molecular weight compounds such as 4-nitroquinoline-N-oxide (> sevenfold) and phleomycin (> 13-fold). In contrast, deletion of genes encoding representative membrane components or membrane transporters had minor effects on cell permeability. We conclude that the yeast cell wall mannoproteins constitute the major barrier to environmental genotoxic agents and that their removal will significantly enhance the sensitivity of RNR-lacZ as well as other yeast-based genotoxic tests.