Microwave-assisted, one-pot syntheses and fungicidal activity of polyfluorinated 2-benzylthiobenzothiazoles

Polyfluorinated 2-benzylthiobenzothiazoles 3a–l are prepared via a microwave-assisted, one-pot procedure. The advantages, such as good to excellent yields, shorter reaction time (14–21 min), readily available starting material, and simple purification procedure, distinguish the present protocol from other existing methods used for the synthesis of 2-benzylthiobenzothiazoles. Bioassay indicated that most of the compounds showed significant fungicidal activity against Rhizoctonia solani, Botrytis cinereapers, and Dothiorella gregaria at a dosage of 50 μg/mL. Interestingly, compared to the control of commercial fungicide, triadimefon, compound 3c exhibited much higher activities against R. solani, B. cinereapers, and D. gregaria, which showed that the polyfluorinated 2-benzylthiobenzothiazoles can be used as lead compound for developing novel fungicides.     

Synthesis, tuberculosis inhibitory activity, and SAR study of N-substituted-phenyl-1,2,3-triazole derivatives

The aim of this work was to describe the synthesis, the in vitro anti-Mycobacterium tuberculosis profile, and the structure–activity relationship (SAR) study of new N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l). The reactions of aromatic amine hydrochlorides with diazomalonaldehyde (1) produced several N-substituted-phenyl-1,2,3-triazole-4-carbaldehydes (3a–l) in moderate-to-good yields. In order to investigate the influence of the difluoromethylene group on the anti-Mycobacterium activity of these compounds, fluorination of triazoles with DAST converted the corresponding carbaldehyde compounds into new difluoromethyl derivatives (4a–l) in excellent yield. Characterization of all compounds was achieved by spectroscopic means and additional for 1-(4-methylphenyl)-1,2,3-triazole-4-carbaldehyde, 3k by X-ray crystallography. Compounds (3a–l) and (4a–l) have been screened for the inhibitory activity against Mycobacterium tuberculosis H37Rv strain (ATCC 27294) and all of them were able to inhibit the growth of the bacterium. Interestingly, 3a and 3k exhibited the best inhibition with MIC values of 2.5 μg/mL, similar to pharmaceuticals currently used in the treatment of tuberculosis. Our SAR study indicated the importance of the hydrogen bond acceptor subunit (3a–l), the position in the aromatic ring, the planarity of triazole and phenyl rings in these compounds, and a correlation between the uniform HOMO coefficient distribution and the anti-tubercular activity. The significant activity of 3a and 3k pointed them as promising lead molecules for further synthetic and biological exploration.     

Depression, comorbid anxiety disorders, and heart rate variability in physically healthy, unmedicated patients: implications for cardiovascular risk

Context

There is evidence that heart rate variability (HRV) is reduced in major depressive disorder (MDD), although there is debate about whether this effect is caused by medication or the disorder per se. MDD is associated with a two to fourfold increase in the risk of cardiac mortality, and HRV is a robust predictor of cardiac mortality; determining a direct link between HRV and not only MDD, but common comorbid anxiety disorders, will point to psychiatric indicators for cardiovascular risk reduction.

Objective

To determine in physically healthy, unmedicated patients whether (1) HRV is reduced in MDD relative to controls, and (2) HRV reductions are driven by MDD alone, comorbid generalized anxiety disorder (GAD, characterized by anxious anticipation), or comorbid panic and posttraumatic stress disorders (PD/PTSD, characterized by anxious arousal).

Design, Setting, and Patients

A case-control study in 2006 and 2007 on 73 MDD patients, including 24 without anxiety comorbidity, 24 with GAD, and 14 with PD/PTSD. Seventy-three MDD and 94 healthy age- and sex-matched control participants were recruited from the general community. Participants had no history of drug addiction, alcoholism, brain injury, loss of consciousness, stroke, neurological disorder, or serious medical conditions. There were no significant differences between the four groups in age, gender, BMI, or alcohol use.

Main Outcome Measures

HRV was calculated from electrocardiography under a standardized short-term resting state condition.

Results

HRV was reduced in MDD relative to controls, an effect associated with a medium effect size. MDD participants with comorbid generalized anxiety disorder displayed the greatest reductions in HRV relative to controls, an effect associated with a large effect size.

Conclusions

Unmedicated, physically healthy MDD patients with and without comorbid anxiety had reduced HRV. Those with comorbid GAD showed the greatest reductions. Implications for cardiovascular risk reduction strategies in otherwise healthy patients with psychiatric illness are discussed.     

Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. Part 7: structure-activity studies of bicyclic 2-pyridone-containing peptidomimetics

The structure-based design, chemical synthesis, and biological evaluation of bicyclic 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. An optimized compound is shown to exhibit antiviral activity when tested against a variety of HRV serotypes (EC(50)'s ranging from 0.037 to 0.162 microM).     

Impact of heart rate variability,a marker for cardiac health,on lupus disease activity

BackgroundDecreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways.MethodsFifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied.ResultsBaseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables.ConclusionsImpaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-016-1087-x) contains supplementary material, which is available to authorized users.     

Design,synthesis and evaluation of 2,2-dimethyl-1,3-dioxolane derivatives as human rhinovirus 3C protease inhibitors

The human rhinovirus (HRV) is the most significant cause of the common cold all over the world. The maturation and replication of this virus entirely depend on the activity of a virus-encoded 3C protease. Due to the high conservation among different serotypes and the minimal homology existing between 3C protease and known mammalian enzymes, 3C protease has been regarded as an attractive target for the treatment of HRV infections. In this study, we identified a novel (4R,5R)-N⁴-(2-((3-methoxyphenyl)amino)ethyl)-2,2-dimethyl-N⁵-(naphthalen-2-yl)-1,3-dioxolane-4,5-dicarboxamide (7a) to be a HRV 3C protease inhibitor via virtual screening. Further research has been focused on the design, synthesis and in vitro biological evaluation of 7a derivatives. The studies revealed that compound 7d has an IC₅₀ value of 2.50 ± 0.7 µM against HRV 3C protease, and it thus could serve as a promising compound for the development of novel anti-rhinoviral medicines.     

Synthesis, spectral studies and in vitro assessment for antiamoebic activity of new cyclooctadiene ruthenium(II) complexes with 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones

We report here the synthesis, characterization and in vitro antiamoebic activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones (TSC), 1–5, and their bidentate complexes [Ru(η⁴-C₈H₁₂)(TSC)Cl₂] 1a–5a. The biological studies of these compounds were investigated against HK-9 strain of Entamoeba histolytica and the concentration causing 50% cell growth inhibition (IC₅₀) was calculated in the micromolar range. The ligands exhibited antiamoebic activity in the range (2.05–5.29 μM). Screening results indicated that the potencies of the compounds increased by the incorporation of ruthenium(II) in the thiosemicarbazones. The complexes 1a–5a showed antiamoebic activity with an IC₅₀ of 0.61–1.43 μM and were better inhibitors of growth of E. histolytica, based on IC₅₀ values. The most promising among them is Ru(II) complex 2a having 1,2,3,4-tetrahydroquinoline as N⁴ substitution.     

Synthesis and antirhinovirus activity of new 3-benzyl chromene and chroman derivatives

A series of 3-benzyl chromenes and chromans were synthesized and tested in vitro against human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. All the new compounds, with the exception of 3-benzyl-2H-chromene (3a), showed a potent activity against HRV serotype 1B within micro or submicromolar range (IC₅₀s from 0.11 to 6.62 μM). The low cytotoxicity of all the derivatives resulted in compounds with high therapeutic index (TI). On the contrary, HRV 14 infection was only weakly inhibited by the majority of these compounds. The 3-benzylidenechromans 2b and 2c showed the highest anti-HRV 1B activity (IC₅₀ 0.12 and 0.11 μM, respectively) coupled with remarkable TI (625.00 and 340.91, respectively). Mechanism of action studies on (Z)-3-(4-chlorobenzylidene)chroman (2b) suggest that the new compounds behave as capsid binders and interfere with very early stages of HRV 1B replication, similarly to related flavanoids.     

Synthesis and anti-rhinovirus activity of novel 3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones

Human rhinoviruses (HRVs) are the most common cause of viral respiratory infections and their complications. So far, no anti-viral agent has been approved for prevention or treatment of HRV infections. Pursuing our researches on small molecules with anti-rhinovirus activity, in this paper we describe the synthesis and in vitro anti-HRV 1B and 14 properties of new [2-(2H-chromen-3-yl)vinyl]pyridines and 3-[2-(pyridinyl)vinyl]-4H-chromen-4-ones. Generally, the synthesized compounds interfered with the replication of both serotypes at the micromolar or submicromolar concentrations. Preliminary results on their mechanism of action, performed on selected (E)-2-[2-(2H-chromen-3-yl)vinyl]pyridine, indicate an interference with the early step(s) of HRV 1B and 14 replication, probably at the uncoating level.     

System analysis of heart rate variability,hemodynamics, and bioelectrical activity of the human brain at moderate altitudes

Heart rate variability (HRV), hemodynamics, cerebral α rhythm, and systemic relations between them have been investigated in 35 normal human subjects at the age of 37.2 ± 3.8 years. The results of comprehensive clinical, functional and instrumental HRV investigation, electroencephalography (EEG) using 21 monopolar electrodes, and blood pressure (BP) monitoring were embodied in mathematical models that describe the relations of these parameters, multiple regression equations, and generated 3D diagrams. It has been found that a relative increase in the LF range and a decrease in HF one are accompanied by elevations of BP. The EEG α amplitude has been depressed, and α index has decreased. The HRV reduction and modification of the α rhythm structure have been demonstrated to affect the BP values. These data indicate interactions and close relations between the autonomic and central nervous systems and BP.     

Human rhinovirus type 2-antibody complexes enter and infect cells via Fc-gamma receptor IIB1

HeLa cells were stably transfected with a cDNA clone encoding the B1 isoform of the mouse FcgammaRII receptor (hereafter referred to as HeLa-FcRII cells). The receptor was expressed at high level at the plasma membrane in about 90% of the cells. These cells bound and internalized mouse monoclonal virus-neutralizing antibodies 8F5 and 3B10 of the subtype immunoglobulin G2a (IgG2a) and IgG1, respectively. Binding of the minor-group human rhinovirus type 2 (HRV2) to its natural receptors, members of the low-density lipoprotein receptor family, is dependent on the presence of Ca(2+) ions. Thus, chelating Ca(2+) ions with EDTA prevented HRV2 binding, entry, and infection. However, upon complex formation of (35)S-labeled HRV2 with 8F5 or 3B10, virus was bound, internalized, and degraded in HeLa-FcRII cells. Furthermore, challenge of these cells with HRV2-8F5 or HRV2-3B10 complexes resulted in de novo synthesis of viral proteins, as shown by indirect immunofluorescence microscopy. These data demonstrate that minor-group receptors can be replaced by surrogate receptors to mediate HRV2 cell entry, delivery into endosomal compartments, and productive uncoating. Consequently, the conformational change and uncoating of HRV2 appears to be solely triggered by the low-pH (pH 相似文献   

Aromatase activity and the effect of estradiol and testosterone on DNA synthesis in endometrial carcinoma cell lines

Human endometrial and breast carcinoma cell lines were examined for aromatase activity and the effects of sex steroids (estradiol and testosterone) on DNA synthesis. Aromatase activity was high (greater than 500 fmol/10⁷ cells/24 h) in the cell lines MCF-7 and OMC-2, moderate (100–499 fmol/10⁷ cells/24 h) in the cell lines HEC-59 and Ishikawa, and low (less than 100 fmol/10⁷ cells/24 h) in the HHUA cell line. A substantial stimulation of DNA synthesis by estradiol (10⁻⁹M) was observed in cell lines HEC-59, OMC-2, and MCF-7, with an increase in [³H]thymidine uptake of over 250%. The Ishikawa cell line was stimulated moderately (115–249%). No estradiol-induced increase in DNA synthesis was observed in HHUA. Responsiveness of DNA synthesis to testosterone was observed in cell lines that showed the greatest response to estradiol, namely HEC-59, OMC-2, and MCF-7. Otherwise, estrogen-responsiveness did not always correlate with a significant aromatase activity. These data suggest that some but not all endometrial carcinomas may possess an aromatase-dependent growth stimulating system.     

Amino acid changes in proteins 2B and 3A mediate rhinovirus type 39 growth in mouse cells

Many steps of viral replication are dependent on the interaction of viral proteins with host cell components. To identify rhinovirus proteins involved in such interactions, human rhinovirus 39 (HRV39), a virus unable to replicate in mouse cells, was adapted to efficient growth in mouse cells producing the viral receptor ICAM-1 (ICAM-L cells). Amino acid changes were identified in the 2B and 3A proteins of the adapted virus, RV39/L. Changes in 2B were sufficient to permit viral growth in mouse cells; however, changes in both 2B and 3A were required for maximal viral RNA synthesis in mouse cells. Examination of infected HeLa cells by electron microscopy demonstrated that human rhinoviruses induced the formation of cytoplasmic membranous vesicles, similar to those observed in cells infected with other picornaviruses. Vesicles were also observed in the cytoplasm of HRV39-infected mouse cells despite the absence of viral RNA replication. Synthesis of picornaviral nonstructural proteins 2C, 2BC, and 3A is known to be required for formation of membranous vesicles. We suggest that productive HRV39 infection is blocked in ICAM-L cells at a step posttranslation and prior to the formation of a functional replication complex. The observation that changes in HRV39 2B and 3A proteins lead to viral growth in mouse cells suggests that one or both of these proteins interact with host cell proteins to promote viral replication.     

The effects of actinomycin D and cordycepin on neurite formation and acetylcholinesterase activity in mouse neuroblastoma cells

Actinomycin D (actD) (0.003–0.10 μg/ml) and cordycepin (3–30 μg/ml) were used to examine the requirement of de novo RNA synthesis in the pH 6.6-induced expression of neurites and acetylcholinesterase activity in C-1300 mouse neuroblastoma cells. ActD at 0.03 and 0.10 μg/ml caused a pronounced stimulation in neurite formation following 20 h of treatment, although by 30 h exposure to actD (0.01–0.10 μg/ml), neurite formation had rapidly declined. Cordycepin (3–30 μg/ml) also inhibited neurite formation in a concentration- and time-dependent manner, although it did not produce an initial stimulation in neurite formation. The pH 6.6-induced increase in acetylcholinesterase activity was inhibited by both actD and cordycepin in a concentration- and time-dependent manner. Cell viabilities in the presence of actD and cordycepin were 90% or greater throughout the course of these studies.The effects of actD on [³H]uridine and [³H]leucine transport into cells and on incorporation into acid-insoluble material showed that actD inhibited RNA synthesis to a greater extent than it inhibited protein synthesis. Cordycepin caused only minor effects on [³H]uridine and [³H]leucine transport into cells and incorporation into acid-insoluble material; these effects were variable and neither concentration- nor time-dependent. The results of this study show that actD can inhibit the pH 6.6-induced expression of neurites and acetylcholinesterase activity in mouse neuroblastoma cells at concentrations which were relatively non-toxic and which caused a greater inhibition of RNA synthesis than of protein synthesis. This suggests that de novo RNA synthesis is required for the expression and maintenance of neurites and acetylcholinesterase activity in mouse neuroblastoma cells. Experiments with cordycepin were consistent with this conclusion.     

Design, synthesis and in vitro evaluation of novel chroman-4-one, chroman, and 2H-chromene derivatives as human rhinovirus capsid-binding inhibitors

As part of an effort to generate broad-spectrum inhibitors of rhinovirus replication, novel series of (E)-3-[(E)-3-phenylallylidene]chroman-4-ones 1a–e, (E)-3-(3-phenylprop-2-yn-1-ylidene)chroman-4-ones 2a and 2b, (Z)-3-[(E)-3-phenylallylidene]chromans 3a–e, and (E)-3-(3-phenylprop-1-en-1-yl)-2H-chromenes 4a–d were designed and synthesized. All the compounds were tested in vitro for their efficacy against infection by human rhinovirus (HRV) 1B and 14, two representative serotypes for rhinovirus group B and A, respectively. Most of the analogues were found to be potent and selective inhibitors of both HRVs, although HRV 1B was generally more susceptible than HRV 14. Mechanism of action studies of (E)-6-chloro-3-(3-phenylprop-1-en-1-yl)-2H-chromene 4b, the most potent compound on HRV 1B infection, suggested that 4b behaves as a capsid-binder probably acting at the uncoating level.     

Effect of oxotremorine,physostigmine, and scopolamine on brain acetylcholine synthesis: A study using HPLC

The synthesis rate of brain acetylcholine (ACh) was estimated in mice following i.v. administration of [³H]choline (Ch). The measurements were performed 1 min after the tracer injection, using the [³H]ACh/[³H]Ch specific radioactivity ratio as an index of ACh synthesis rate. Endogenous and labeled Ch and ACh were quantified using HPLC methodology. Oxotremorine and physostigmine (0.5 mg/kg, i.p.) increased the steady state concentration of brain ACh by +130% and 84%, respectively and of Ch by +60% (oxotremorine); they decreased ACh synthesis by 62 and 55%, respectively. By contrast, scopolamine (0.7 mg/kg, i.p.) decreased the cerebral content of Ch by –26% and of ACh by –23% without enhancing the synthesis of ACh. The results show the utility of HPLC methodology in the investigation of ACh turnover.     

Three-dimensional quantitative structure–activity relationship (3D-QSAR) of 3-aryloxazolidin-2-one antibacterials

Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies for 3-aryloxazolidin-2-one antibacterials were performed using the genetic function approximation algorithm. This study was performed using 60 compounds, in which the QSAR models were developed using a training set of 50 compounds. The in vitro minimum inhibitory concentration (MIC) against Staphylococcus aureus SFCO-1a was used for the study. The predictive ability of the QSAR model was evaluated by using a test set of 10 compounds. The statistical quality of the QSAR models was assessed using statistical parameters r², r²_cv (cross-validated r²), r²_pred (predictive r²) and lack of fit measure (LOF). The results obtained indicate that the antibacterial activity of the 3-aryloxazolidin-2-ones is strongly dependent on electronic factor as expressed by lowest unoccupied molecular orbital energy (LUMO), spatial factor as expressed by density and thermodynamic factors accounted for by molar refractivity and heat of formation. The model is presently being used to design and predict new potent molecules prior to synthesis.     

Antiviral activity of raoulic acid from Raoulia australis against Picornaviruses

RNA viruses are a major source of respiratory diseases worldwide. The lack of effective therapeutical treatment underlines the importance of research for new antiviral compounds. Raoulic acid is a principal ingredient of the plant Raoulia australis Hook. F. Antiviral assay using cytopathic effect (CPE) reduction method showed that raoulic acid possessed strong antiviral activity against human rhinovirus 2 (HRV2) with a 50% inhibition concentration (IC₅₀) value of less than 0.1 μg/ml, human rhinovirus 3 (HRV3) with a IC₅₀ value of 0.19 μg/ml, coxsackie B3 (CB3) virus with IC₅₀ values of 0.33 μg/ml, coxsackie B4 (CB4) virus with IC₅₀ values of 0.40 μg/ml, and enterovirus 71 (EV71) virus with IC₅₀ values of less than 0.1 μg/ml. However, the compound did not possess antiviral activity against influenza A (Flu A/PR, Flu A/WS, H1N1) and B viruses at four concentrations ranging from 0.1 to 100 μg/ml.     

Wortmannin delays transfer of human rhinovirus serotype 2 to late endocytic compartments

Human rhinovirus 2 (HRV2) is internalized by members of the low-density lipoprotein receptor family into early endosomes (pH 6.2-6.0) where it dissociates from its receptors. After transfer into late endosomes, the virus undergoes a conformational change and RNA uncoating solely induced by pH < 5.6. Finally, virus capsids are degraded in lysosomes. To investigate the role of phosphatidylinositol 3-kinases (PI3K) in the HRV2 entry route, we used the inhibitor wortmannin. Although virus internalization was not altered by wortmannin, virus accumulated in enlarged early endosomes. Furthermore, the drug delayed HRV2 degradation and viral protein synthesis. Consequently, wortmannin-sensitive PI3K are involved in HRV2 transport from early to late compartments. However, wortmannin had no effect on the titer of infectious virus produced. Our data therefore suggest that virus retained in early endosomes for prolonged time periods can undergo the conformational change that otherwise occurs at pH < or = 5.6 in late endosomes.