Identification Of New Compounds Research Articles

Insights into RNA-dependent RNA Polymerase Inhibitors as Antiinfluenza Virus Agents.

Influenza is a seasonal disease that affects millions of people every year and has a significant economic impact. Vaccines are the best strategy to fight this viral pathology, but they are not always available or administrable, prompting the search for antiviral drugs. RNA-dependent RNA polymerase (RdRp) recently emerged as a promising target because of its key role in viral replication and its high conservation among viral strains. This review presents an overview of the most interesting RdRp inhibitors that have been discussed in the literature since 2000. Compounds already approved or in clinical trials and a selection of inhibitors endowed with different scaffolds are described, along with the main features responsible for their activity. RdRp inhibitors are emerging as a new strategy to fight viral infections and the importance of this class of drugs has been confirmed by the FDA approval of baloxavir marboxil in 2018. Despite the complexity of the RdRp machine makes the identification of new compounds a challenging research topic, it is likely that in the coming years, this field will attract the interest of a number of academic and industrial scientists because of the potential strength of this therapeutic approach.

Synthesis and Identification of new compounds have Antioxidant activity Beta-carotene, from Natural Auxin Phenyl Acetic Acid

For the purpose of synthetic compounds active anti-oxidation in plants. At the same time, these synthesized compounds a harmless and not damaged or affect the rapid growth of plants. Phenyl acetic acid was chosen as a nucleus to synthesize compounds used in this study, this compound was chosen because it is considered an important auxin for plant growth. These compounds were tested as antioxidants, and were found to be effective as antioxidants The antioxidant capacity was evaluated by β-carotene/linoleic acid assay. Results showed that 60% of these derivatives have antioxidant activity, exhibiting 50, 57% to 78, 96% inhibitions. Physical characterization of these synthesized compounds, which were established by performing melting point and Rf 13C NM, value. The derivative structures were identified using UV, FT-IR, and HNMR, 13C-DEPT spectral analysis.

English

Essential oil from plants belonging to several species has been extensively used as natural resources in the prevention and treatment of a large number of diseases. The medicinal and aromatic plants of genus Etlingera produces high percentages of essential oil from its every organ and is recommended for a variety of health problems by traditional systems of medicine in south-east Asia. Essential oils from this genus demonstrated promising antimicrobial properties. As antibiotic resistance is emerging at an alarming rate, many infectious diseases have become difficult to treat. Thus, the genus Etlingera can be considered as a good source of essential oils, and extensive studies of biological activities of these oils may lead to the identification of new compounds which can be used in modern medicine, cosmetics and pharmaceutical industry, primarily as antimicrobial agents. This review summarizes the characteristics of essential oil of Etlingera species with particular attention to the chemical composition and antimicrobial activities from the data in the recent literature. Key words: Etlingera, essential oil, chemical composition, antimicrobial activity.

Screening oxime libraries by means of mass spectrometry (MS) binding assays: Identification of new highly potent inhibitors to optimized inhibitors γ-aminobutyric acid transporter 1.

Generation and screening of oxime libraries by competitive MS Binding Assays represents a powerful tool for the identification of new compounds, with affinity to mGAT1, the most abundant plasma membrane bound GABA transporter in the CNS. By screening a guvacine derived oxime library, new potent inhibitors of mGAT1 had been revealed. In the present study, oxime libraries generated by reaction of a large excess of a rac-nipecotic acid derivative displaying a hydroxylamine functionality in which various aldehydes under suitable conditions, were examined for new potent inhibitors of mGAT1. The pKi values obtained of the best hits were compared with those of related compounds displaying a guvacine instead of a nipecotic acid subunit as hydrophilic moiety. Amongst the new compounds one of the most affine ligands of mGAT1 known so far (pKi = 8.55 ± 0.04) was found.

Brazilian Biodiversity Fruits: Discovering Bioactive Compounds from Underexplored Sources.

Large segments of the Brazilian population still suffer from malnutrition and diet-related illnesses. In contrast, many native fruits have biodiversity and are underexploited sources of bioactive compounds and unknown to consumers. The phytochemical composition of nine underexplored Brazilian fruits was determined. Carotenoids and anthocyanins were identified and quantified by high performance liquid chromatography-photodiode array-tandem mass spectrometry (HPLC-PDA-MS/MS), and phenolic compounds and iridoids were identified by flow injection analysis-electrospray-ion trap-tandem mass spectrometry (FIA-ESI-IT-MS/MS); in total, 84 compounds were identified. In addition, the chemical structure and pathway mass fragmentation of new iridoids from jenipapo ( Genipa americana) and jatoba ( Hymenae coubaril) are proposed. The highest level of carotenoids was registered in pequi ( Caryocar brasiliense; 10156.21 μg/100 g edible fraction), while the major total phenolic content was found in cambuci ( Campomanesia coubaril; 221.70 mg GAE/100 g). Anthocyanins were quantified in jabuticaba ( Plinia cauliflora; 45.5 mg/100 g) and pitanga ( Eugenia uniflora; 81.0 mg/100 g). Our study illustrates the chemical biodiversity of underexplored fruits from Brazil, supporting the identification of new compounds and encouraging the study of more food matrixes not yet investigated.

Identification of Potential Nematicidal Compounds against the Pine Wood Nematode, Bursaphelenchus xylophilus through an In Silico Approach.

Bursaphelenchus xylophilus is a destructive phytophagous nematode that mainly infects pine species and causes pine wilt disease (PWD). PWD is one of the most devastating diseases that has damaged the pine forests of eastern Asia and Portugal for the last four decades. B. xylophilus infects healthy pine trees through Monochamus beetles and its subsequent proliferation results in destruction of the infected pine trees. The poor water solubility and high cost of currently used trunk-injected chemicals such as avermectin and abamectin for the prevention of PWD are major concerns. Thus, for the identification of new compounds targeting the different targets, five proteins including cathepsin L-like cystein proteinase, peroxiredoxins, hsp90, venome allergen protein and tubulin that are known to be important for development and pathogenicity of B. xylophilus were selected. The compounds were virtually screened against five proposed targets through molecular docking into hypothetical binding sites located in a homology-built protein model. Of the fifteen nematicides screened, amocarzine, mebendazole and flubendazole were judged to bind best. For these best docked compounds, structural and electronic properties were calculated through density functional theory studies. The results emphasize that these compounds could be potential lead compounds that can be further developed into nematicidal chemical against B. xylophilus. However, further studies are required to ascertain the nematicidal activity of these compounds against phytophagous nematode.

Design, Synthesis, And Biological Evaluation of G Protein‐Coupled Estrogen Receptor (GPR30/GPER) Ligands That Contribute to The First Structure‐Activity‐Relationship for The Receptor

The development of G Protein-Coupled Estrogen receptor (GPR30/GPER) agonists and antagonists has been hampered by an insufficient understanding of binding modes and interactions. Our group has previously described the first structure-activity relationship (SAR) of GPR30/GPER. During these studies we identified key interactions and have utilized the information in the development of a new series of compounds. Each compound in the new series was assessed for therapeutic value with various functional assays. To ensure selectivity, nuclear estrogen receptor binding studies were also performed. Overall, the identification of new compounds with improved selectivity and binding will enable a better understanding of not only the pharmacology of GPR30/GPER but also the role of the receptor in various models of disease. Support or Funding Information Saint Louis University This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Identification of New Compounds from Sage Flowers (Salvia officinalis L.) as Markers for Quality Control and the Influence of the Manufacturing Technology on the Chemical Composition and Antibacterial Activity of Sage Flower Extracts

Parts of Salvia species such as its flowers and leaves are currently used as a culinary herb and for some medicinal applications. To distinguish the different sage extracts it is necessary to analyze their individual chemical compositions. Their characteristic compounds might be established as markers to differentiate between sage flowers and leaf extracts or to determine the manufacturing technology and storage conditions. Tri-p-coumaroylspermidine can be detected only in flowers and has been described here for Salvia and Lavandula species for the first time. Markers for oxidation processes are the novel compounds salviquinone A and B, which were generated from carnosol by exposure to oxygen. Caffeic acid ethyl ester was established as an indirect marker for the usage of ethanol as extraction solvent. The compounds were identified by LC-QTOF-HRESIMS, LC-MS, NMR, IR, and single-crystal X-ray diffraction after isolation by semipreparative HPLC. Furthermore, sage flower resin showed interesting antibacterial in vitro activities against Gram-positive and Gram-negative bacteria.

Prediction of collision cross section and retention time for broad scope screening in gradient reversed-phase liquid chromatography-ion mobility-high resolution accurate mass spectrometry

Exact mass, retention time (RT), and collision cross section (CCS) are used as identification parameters in liquid chromatography coupled to ion mobility high resolution accurate mass spectrometry (LC-IM-HRMS). Targeted screening analyses are now more flexible and can be expanded for suspect and non-targeted screening. These allow for tentative identification of new compounds, and in-silico predicted reference values are used for improving confidence and filtering false-positive identifications. In this work, predictions of both RT and CCS values are performed with machine learning using artificial neural networks (ANNs). Prediction was based on molecular descriptors, 827 RTs, and 357 CCS values from pharmaceuticals, drugs of abuse, and their metabolites. ANN models for the prediction of RT or CCS separately were examined, and the potential to predict both from a single model was investigated for the first time. The optimized combined RT-CCS model was a four-layered multi-layer perceptron ANN, and the 95th prediction error percentiles were within 2 min RT error and 5% relative CCS error for the external validation set (n = 36) and the full RT-CCS dataset (n = 357). 88.6% (n = 733) of predicted RTs were within 2 min error for the full dataset. Overall, when using 2 min RT error and 5% relative CCS error, 91.9% (n = 328) of compounds were retained, while 99.4% (n = 355) were retained when using at least one of these thresholds. This combined prediction approach can therefore be useful for rapid suspect/non-targeted screening involving HRMS, and will support current workflows.

Functional Analogues of Salicylic Acid and Their Use in Crop Protection

Functional analogues of salicylic acid are able to activate plant defense responses and provide attractive alternatives to conventional biocidal agrochemicals. However, there are many problems that growers must consider during their use in crop protection, including incomplete disease reduction and the fitness cost for plants. High-throughput screening methods of chemical libraries allowed the identification of new compounds that do not affect plant growth, and whose mechanisms of action are based on priming of plant defenses, rather than on their direct activation. Some of these new compounds may also contribute to the discovery of unknown components of the plant immune system.

Characterization of tyrosinase inhibitory constituents from the aerial parts of Humulus japonicus using LC-MS/MS coupled online assay

In the screening of natural products for the development as cosmetic ingredients, the EtOAc-soluble fraction of Humulus japonicus showed tyrosinase inhibitory activity. HPLC-MS/MS coupled online tyrosinase assay of EtOAc-soluble fraction of H. japonicus characterized the twenty-eight constituents including two unknown ones and their tyrosinase inhibitory activity. Fractionation of H. japonicus using various chromatographic techniques yielded thirty-eight compounds. The chemical structures of isolated compounds were identified by spectroscopic analysis. As characterized by HPLC-MS/MS analysis, we isolated twenty-four predicted compounds and further identified two unknown ones, named humulusides A (1) and B (2). Additional ten compounds were also identified by purification. Tyrosinase inhibitory activity of isolated compounds were evaluated, which was closely correlated with the results from HPLC-MS/MS coupled online tyrosinase assay. Consistent with predicted data, two major compounds, trans-N-coumaroyltyramine (14) and cis-N-coumaroyltyramine (15) showed tyrosinase inhibition with IC50 values of 40.6 and 36.4 μM. Taken together, H. japonicus is suggested as whitening ingredient in cosmetic products. In addition, HPLC-MS/MS coupled tyrosinase assay is powerful tool for predicting active compounds with short time and limited amounts, although identification of new compounds and verification of predicted data are also needs to be demonstrated by further experiment.

Pharmacokinetic drug evaluation of pazopanib for the treatment of uterine leiomyosarcomas

ABSTRACTIntroduction: Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy.Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS.Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.

In vitroandin vivo antibacterial activities of rhizophora man-gle l. against helicobacter pylori. chemical compounds elucida-tion

Rhizophora mangle L. is a vegetal species widely distributed in Cuba and other Caribbean countries with ethno- pharmacology relevance and preview reports as antiulcer and wound healing properties. The present work describes the in vitro and in vivo antibacterial activities of dried aqueous extract of bark and polyphenol fractions from R. mangle against Helicobacter pylori and the identification of new compounds in the active extracts. Minimum inhibitory concentration (MIC) and Minimum bactericide concentration (MBC) were evaluated against reference and clinical Helicobacter pylori strains with total extract, High Molecular Weight and Low Molecular Weight fractions isolated from total extract. Positive active fractions in vitro tests were evaluated in vivo using H. pylori C57BL/6 mice. Fractionation, isolation and structural elucidation of the compounds on High Molecular Weigh fraction and on Low Molecular Weight fraction were made using Chromatography methods and Mass and H+NMR spectrometry. Total aqueous extract from bark of R. mangle and some fraction shown promissory antibacterial activity on in vitro and in vivo models. It was isolated and identified proantocyanidin, catechin and epicatechin derivates, cyanidin and other compounds in this promissory extract. These results appoint to total extract with a promissory active principle in the development of phytodrug with antibacterial effect and as proton pump inhibitor by the treatment of gastroduodenal ulcer.

Antimicrobial structure activity relationship of five anthraquinones of emodine type isolated from Vismia laurentii

BackgroundAntimicrobial activity of anthraquinone compounds of emodine type has been reported by many authors. These compounds are found in Vismia laurentii (Clusiaceae), a plant used in traditional pharmacopoeia for treatment of microbial infections among others affections. The continuous identification of new compounds has raised the problem of the relation between the structure and antimicrobial properties.ResultsThe yeast growth kinetics parameters were not influenced by the pH variation as it was the case for the other tested bacteria. Fungicidal activities were noted for all molecules while only few of them had bactericidal activities, mostly on Gram positive bacteria. Mathematical model establishing a quantitative relationship between physicochemical properties of molecules and their fungicidal activities were obtained for Candida albicans and showed that physicochemical properties impacting on antifungal activity were polarizability, partition coefficient, molecular weight and hydrogen bond acceptor.ConclusionsThis work demonstrated that the presence of a long aliphatic chain methoxy group substituted in position two of the emodine structure increased the antibacterial properties of the studied compounds. Moreover this antimicrobial property depends on the pH of the environment, and specifically on the polarizability and number of hydrogen bond acceptors of the compound.

A Tryptoline Ring-Distortion Strategy Leads to Complex and Diverse Biologically Active Molecules from the Indole Alkaloid Yohimbine.

High-throughput screening (HTS) is the primary driver to current drug-discovery efforts. New therapeutic agents that enter the market are a direct reflection of the structurally simple compounds that make up screening libraries. Unlike medically relevant natural products (e.g., morphine), small molecules currently being screened have a low fraction of sp3 character and few, if any, stereogenic centers. Although simple compounds have been useful in drugging certain biological targets (e.g., protein kinases), more sophisticated targets (e.g., transcription factors) have largely evaded the discovery of new clinical agents from screening collections. Herein, a tryptoline ring-distortion strategy is described that enables the rapid synthesis of 70 complex and diverse compounds from yohimbine (1); an indole alkaloid. The compounds that were synthesized had architecturally complex and unique scaffolds, unlike 1 and other scaffolds. These compounds were subjected to phenotypic screens and reporter gene assays, leading to the identification of new compounds that possessed various biological activities, including antiproliferative activities against cancer cells with functional hypoxia-inducible factors, nitric oxide inhibition, and inhibition and activation of the antioxidant response element. This tryptoline ring-distortion strategy can begin to address diversity problems in screening libraries, while occupying biologically relevant chemical space in areas critical to human health.

Identification of new compounds from Fumaria parviflora Lam.

Isolation of wound healing compounds from Heliotropium indicumDodehe Yeo, Barthélémy Attioua, Christine Lehalle, Metowogo Kossi, Jean David N’guessan, Allico Joseph Djaman, Annelise Lobstein, Nelly Frossard

Interactions of aminoglycosides with RNAs and proteins via carbohydrate microarray

Aminoglycosides are broad-spectrum antibacterials to treat bacterial infections, especially gram-negative bacteria infections. However, aminoglycosides are losing efficacy because of the increase in antibiotic resistance and their inherent toxicity, attracting more interests in developing new aminoglycosides. Several clinically used aminoglycosides are mainly exerted by inhibition of protein synthesis through binding to bacterial rRNA. The bacterial ribosome RNA is the most currently exploited RNA drug target. Identification of new compounds that target RNAs is indispensable to fight with the growing threat that bacteria pose to human safety. In this work, we used carbohydrate microarrays to probe interactions of low molecular weight ligands with RNAs and proteins. Carbohydrate microarrays, comprising hundreds to thousands of different glycan structures on surfaces in a spatially discrete pattern, are sensitive and versatile tools to study the interactions between biological macromolecules. Herein, aminoglycosides have been immobilized onto the modified glass microscope slides and their interactions with RNAs and proteins are then measured through the labeled fluorescence. The results displayed that microarray can be used to detect the binding of aminoglycosides with three types of target molecules, including the small RNA oligonucleotide mimics of aminoglycoside binding sites in the ribosome (rRNA A-site mimics), the large group I ribozyme RNA (approximately 400 nucleotide) and certain proteins (toxicity-causing enzymes, such as DNA polymerase and phospholipase C). For rRNA A-site mimics, the fluorescence intensities of 16S rRNA is stronger than that of 18S rRNA, illustrating that as a screen technique, the microarray method can not only determine the binding affinity to RNA but also detect the specific binding to bacterial rRNA mimic. The ability to screen group I ribozyme RNA can be helpful to the discovery of new RNA therapeutic targets. Binding of immobilized aminoglycosides to toxicity-causing proteins (DNA polymerase and phospholipase C) is a new method to study of aminoglycoside toxicity. These studies lay the foundation for rapid identification of new RNA-binding ligands with strong and specific binding affinity for their desired targets.

Design, synthesis and pharmacological evaluation of new anti-inflammatory compounds

Inflammatory diseases and pain are among the main problems that significantly influence the lifestyle of millions of people and existing therapies are not always effective and can cause several adverse effects. In this context, the molecular modifications or synthesis of compounds continue being the best strategies for the identification of new compounds for the treatment of pain and inflammation. The aim of this study was to evaluate the analgesic and anti-inflammatory activities of new analogues of pyrazole compounds containing subunits N-phenyl-1-H-pirazoles and 1,3,4-oxadiazole-2(3H)-thione, LQFM-146, LQFM-147 and LQFM-148. In the acetic acid-induced abdominal writhing test, treatments with LQFM-146, LQFM-147 or LQFM-148 at doses 89, 178 and 356µmol/kg p.o. reduced the abdominal writhing in a dose-dependent manner. In the formalin test, these compounds at dose 178µmol/kg p.o. reduced the licking time only in inflammatory phase of this test, suggesting an antinociceptive effect dependent of the anti-inflammatory effect. The treatment with the three compounds in intermediate dose (178µmol/kg p.o.) reduced the edema at all tested time points in the carrageenan-induced paw edema test and reduced polymorphonuclears cell migration, activity myeloperoxidase and TNF-α levels in the carrageenan-induced pleurisy test. Our date suggest that the new compounds LQFM-146, LQFM-147 and LQFM-148 possess satisfactory anti-inflammatory and antinociceptive effects that involves the reduction of pro-inflammatory cytokines and inhibition of the myeloperoxidase enzyme.

Abstract 364: Validation of human osteoclast cultures for studying the mode-of-action and identification of new compounds with the potential of inhibiting the vicious cycle in osteolytic bone metastases

Abstract When tumor cells home to bone microenvironment they secrete factors that stimulate osteoclast formation, which results in increased bone resorption. This in turn increases the release of factors from bone matrix that stimulate the growth of tumor cells, leading to a vicious cycle characterized by extensive bone loss and enhanced tumor growth in bone. Thus, factors that inhibit osteoclast formation or bone resorption activity of mature osteoclasts may have the potential to inhibit the vicious cycle. The RANKL inhibitor denosumab is approved for treatment of bone metastases from solid tumors, and the cathepsin K inhibitor odanacatib has been shown to suppress bone resorption in breast cancer patients with bone metastases. Human osteoclasts can be generated from bone marrow-derived CD34+ mesenchymal stem cells in the presence of M-CSF and RANKL. In this study we report optimization of separate in vitro culture systems for determining osteoclast differentiation and activity, and validation of denosumab and odanacatib as reference inhibitors of osteoclast differentiation and activity, respectively. CD34+ human osteoclast precursor cells were cultured on bovine bone slices for 7 days. Different concentrations of denosumab (0.01 - 10 μg/ml) were added in the cultures at day 0, and tartrate-resistant acid phosphatase isoform 5b activity (TRACP 5b) was measured from the culture medium collected at day 7 as an index of the number of formed osteoclasts. Osteoclast activity was studied by allowing the formed mature osteoclasts to resorb bone during an additional 3-day culture period. The culture medium was changed and different concentrations of odanacatib (0.001 - 1.0 μM) were added into the cultures at day 7, and the amount of C-terminal cross-linked telopeptides of type I collagen (CTX-I) was measured in the culture medium collected at day 10 to quantitate bone resorption during days 7-10. Denosumab and odanacatib showed strong concentration dependent inhibition of osteoclast differentiation and activity, respectively, with EC50 values of 0.124 μg/ml for denosumab and 0.0433 μM for odanacatib. We conclude that we have validated denosumab as a reference compound of osteoclast differentiation and odanacatib as a reference compound of osteoclast activity in a human in vitro osteoclast culture system. The culture system is a clinically reliable tool for identifying new compounds affecting the vicious cycle of osteolytic bone metastases, and clarifying if these active compounds target directly osteoclast differentiation or activity. Citation Format: Jenni Bernoulli, Jussi M. Halleen, Mari I. Suominen, Johanna Tuomela, Jukka Rissanen, Katja M. Fagerlund. Validation of human osteoclast cultures for studying the mode-of-action and identification of new compounds with the potential of inhibiting the vicious cycle in osteolytic bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 364.

The Zebrafish, a Novel Model Organism for Screening Compounds Affecting Acute and Chronic Ethanol-Induced Effects.

Alcohol addiction is a major unmet medical and economic issue for which very few efficacious pharmacological treatment options are currently available. The development and identification of new compounds and drugs to treat alcohol addiction is hampered by the high costs and low amenability of traditional laboratory rodents to high-throughput behavioral screens. The zebrafish represents an excellent compromise between systems complexity and practical simplicity by overcoming many limitations inherent in these rodent models. In this chapter, we review current advances in the behavioral and neurochemical characterization of ethanol-induced changes in zebrafish. We also discuss the basic principles and methods of and the most recent advances in using paradigms with which one can screen for compounds altering acute and chronic ethanol-induced effects in zebrafish.