- Pentuline derivatives and preparation methods and applications thereof
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The present invention provides a chingotine derivative, the structural formula of which is shown in formula I. Specifically, the R is any of the following groups: p-chlorophenylacetyl, 2,4-dichlorophenylacetyl, m-chlorophenylacetyl, 3,4-dichlorophenylacet
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Paragraph 0046-0050
(2022/01/12)
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- Identification of BR102910 as a selective fibroblast activation protein (FAP) inhibitor
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Fibroblast activation protein (FAP) belongs to the family of prolyl-specific serine proteases and displays both exopeptidase and endopeptidase activities. FAP expression is undetectable in most normal adult tissues, but is greatly upregulated in sites of tissue remodeling, which include fibrosis, inflammation and cancer. Due to its restricted expression pattern and dual enzymatic activities, FAP inhibition is investigated as a therapeutic option for several diseases. In the present study, we described the structure–activity relationship of several synthesized compounds against DPPIV and prolyl oligopeptidase (PREP). In particular, BR102910 (compound 24) showed nanomolar potency and high selectivity. Moreover, the in vivo FAP inhibition study of BR102910 (compound 24) using C57BL/6J mice demonstrated exceptional profiles and satisfactory FAP inhibition efficacy. Based on excellent in vitro and in vivo profiles, the potential of BR102910 (compound 24) as a lead candidate for the treatment of type 2 diabetes is considered.
- Jung, Hui Jin,Nam, Eun Hye,Park, Jin Young,Ghosh, Prithwish,Kim, In Su
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supporting information
(2021/02/26)
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- Design, synthesis, biological evaluation and silico prediction of novel sinomenine derivatives
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Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty‐three compounds were synthesized and characterized by spectroscopy (IR,1H‐NMR,13C‐NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF‐7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine‐containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer‐related core targets and verified their interaction with derivatives through molecular docking. The chlorine‐containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine‐containing derivatives might be a promising lead for the development of new anticancer agents.
- Cui, Dongmei,Gao, Mingjie,Li, Jinjie,Li, Shoujie,Nian, Xin,Zhang, Chen,Zhang, Liyu,Zhao, Changqi
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- Structure-activity relationships of agonists for the orphan G protein-coupled receptor GPR27
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GPR27 belongs, with GPR85 and GPR173, to a small subfamily of three receptors called “Super-Conserved Receptors Expressed in the Brain” (SREB). It has been postulated to participate in key physiological processes such as neuronal plasticity, energy metabolism, and pancreatic β-cell insulin secretion and regulation. Recently, we reported the first selective GPR27 agonist, 2,4-dichloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (I, pEC50 6.34, Emax 100%). Here, we describe the synthesis and structure-activity relationships of a series of new derivatives and analogs of I. All products were evaluated for their ability to activate GPR27 in an arrestin recruitment assay. As a result, agonists were identified with a broad range of efficacies including partial and full agonists, showing higher efficacies than the lead compound I. The most potent agonist was 4-chloro-2,5-difluoro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7y, pEC50 6.85, Emax 37%), and the agonists with higher efficacies were 4-chloro-2-methyl-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7p, pEC50 6.04, Emax 123%), and 2-bromo-4-chloro-N-(4-(N-phenylsulfamoyl)phenyl)benzamide (7r, pEC50 5.99, Emax 123%). Docking studies predicted the putative binding site and interactions of agonist 7p with GPR27. Selected potent agonists were found to be soluble and devoid of cellular toxicity within the range of their pharmacological activity. Therefore, they represent important new tools to further characterize the (patho)physiological roles of GPR27.
- Blavier, Jeremy,Charles, Ma?lle,Hanson, Julien,Kronenberger, Thales,Laschet, Céline,Müller, Christa E.,Pillaiyar, Thanigaimalai,Rosato, Francesca,Wozniak, Monika
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- Quantitative activity-activity relationship (QAAR) driven design to develop hydroxamate derivatives of pentanoic acids as selective HDAC8 inhibitors: synthesis, biological evaluation and binding mode of interaction studies
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Histone deacetylase 8 (HDAC8) has been implicated as a potential drug target of many diseases including cancer. HDAC8 isoform selectivity over other class-I HDACs is a major concern nowadays. In this work, a series of pentanoic acid based hydroxamates wit
- Adhikari, Nilanjan,Amin, Sk. Abdul,Das, Sanjib,Ghosh, Balaram,Jha, Tarun,Routholla, Ganesh,Trivedi, Prakruti,Vijayasarathi, Dhanya
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p. 17149 - 17162
(2021/10/04)
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- N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation
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A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 μM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10?3 s?1) from the catalytic domain.
- Fang, Hai-Lian,He, Jie-Ling,Li, Wei-Yi,Liu, Shan-Shan,Ni, Wei-Wei,Pan, Xing-Ming,Xiao, Zhu-Ping,Ye, Ya-Xi,Yi, Juan,Zhou, Mi,Zhou, Tian-Li,Zhu, Hai-Liang
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p. 404 - 413
(2020/01/03)
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- Palladium-Catalyzed 2-(Neopentylsulfinyl)aniline Directed C–H Acetoxylation and Alkenylation of Arylacetamides
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The 2-(neopentylsulfinyl)aniline directing group that promotes rapid palladium-catalyzed C–H acetoxylation and alkenylation of arylacetamides has been developed. The acetoxylation reaches completion within only 40 min at 100 °C and leads to the bis-functionalized products. Alternatively, the reaction can be carried out at room temperature, which is beneficial for sensitive substrates. For the alkenylation, we have developed a protocol in which easily available 1-substituted cyclopropanols were employed as equivalents of vinyl ketones.
- Barysevich, Maryia V.,Laktsevich-Iskryk, Marharyta V.,Krech, Anastasiya V.,Zhabinskii, Vladimir N.,Khripach, Vladimir A.,Hurski, Alaksiej L.
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supporting information
p. 937 - 943
(2020/02/25)
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- Discovery of γ-Lactam alkaloid derivatives as potential fungicidal agents targeting steroid biosynthesis
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Biological control of plant pathogens is considered as one of the green and effective technologies using beneficial microorganisms or microbial secondary metabolites against plant diseases, and so microbial natural products have played important roles in the research and development of new and green agrochemicals. To explore the potential applications for natural γ-lactam alkaloids and their derivatives, 26 γ-lactams that have flexible substituent patterns were synthesized and characterized, and their in vitro antifungal activities against eight kinds of plant pathogens belonging to oomycetes, basidiomycetes, and deuteromycetes were fully evaluated. In addition, the high potential compounds were further tested using an in vivo assay against Phytophthora blight of pepper to verify a practical application for controlling oomycete diseases. The potential modes of action for compound D1 against Phytophthora capsici were also investigated using microscopic technology (optical microscopy, scanning electron microscopy, and transmission electron microscopy) and label-free quantitative proteomics analysis. The results demonstrated that compound D1 may be a potential novel fungicidal agent against oomycete diseases (EC50 = 4.9748 μg·mL-1 for P. capsici and EC50 = 5.1602 μg·mL-1 for Pythium aphanidermatum) that can act on steroid biosynthesis, which can provide a certain theoretical basis for the development of natural lactam derivatives as potential antifungal agents.
- Cao, Xiufang,Huang, Daye,Huang, Wenbo,Ke, Shaoyong,Song, Di,Wang, Shuangshuang
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p. 14438 - 14451
(2020/12/23)
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- Optimization of methionyl tRNA-synthetase inhibitors for treatment of Cryptosporidium infection
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Cryptosporidiosis is one of the leading causes of moderate to severe diarrhea in children in low-resource settings. The therapeutic options for cryptosporidiosis are limited to one drug, nitazoxanide, which unfortunately has poor activity in the most need
- Buckner, Frederick S.,Ranade, Ranae M.,Robert Gillespie,Shibata, Sayaka,Hulverson, Matthew A.,Zhang, Zhongsheng,Huang, Wenlin,Choi, Ryan,Verlinde, Christophe L.M.J.,Hol, Wim G.J.,Ochida, Atsuko,Akao, Yuichiro,Choy, Robert K.M.,Van Voorhis, Wesley C.,Arnold, Sam L.M.,Jumani, Rajiv S.,Huston, Christopher D.,Fan, Erkang
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supporting information
(2019/04/04)
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- Synthesis of novel nicotinic ligands with multimodal action: Targeting Acetylcholine α4β2, Dopamine and Serotonin Transporters
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Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4β2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 μM for h-DAT and 0.031 ± 0.006 μM for α4β2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 μM for α4β2 nAChR and 0.075 ± 0.009 μM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4β2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/β2 subunit interfaces of α4β2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.
- González-Gutiérrez, Juan Pablo,Pessoa-Mahana, Hernán Armando,Iturriaga-Vásquez, Patricio Ernesto,Reyes-Parada, Miguel Iván,Guerra-Díaz, Nicolas Esteban,Hodar-Salazar, Martin,Viscarra, Franco,Paillali, Pablo,Nú?ez-Vivanco, Gabriel,Lorca-Carvajal, Marcos Antonio,Mella-Raipán, Jaime,Zú?iga, María Carolina
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- Method for synthesizing 2,4-dichlorophenyl acetylchloride
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The invention discloses a method for synthesizing 2,4-dichlorophenyl acetylchloride and relates to the technical field of organic synthesis. The synthetic method comprises the following steps of dissolving 2,4-dichlorophenyl acetic acid into dichloroethane, slowly dropwise adding triphosgene, controlling temperature not to exceed 40 DEG C, performing reaction for 1h, and removing a solvent with pressure reduction to obtain 2,4-dichlorophenyl acetylchloride as a product. The synthetic method has the main advantages that the quality of the product is improved, and the yield of the product is increased; and meanwhile, as a by-product is carbon dioxide, thionyl chloride is avoided from being used for producing a great quantity of waste acid, and the technology is environmentally friendly.
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Paragraph 0017-0024
(2018/12/13)
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- Heterocyclic pyrrolizinone and indolizinones derived from natural lactam as potential antifungal agents
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With the aim to develop highly potential active heterocyclic compounds, two series of multi-substituted pyrrolizinone and indolizinones derived from lactam were designed, synthesized and evaluated for their potential antifungal activities against six species of the plant pathogen fungi (Fusarium graminearum, Sclerotinia sclerotiorum, Phomopsis adianticola, Gloeosporium theae-sinensis, Alternaria tenuis Nees, Magnaporthe oryzae). The structure of all the newly molecules were confirmed by analytical spectroscopic data, including 1H NMR, 13C NMR and ESI-MS. According to the preliminary studies on bio-evaluation assay, some of the obtained compounds exhibited moderate and broad-spectrum activities against six fungi compared to the intermediates 6a, 6f and the hymexazol. Particularly, the inhibition rate of compounds 7l, 7m and 7t reached 69.25%, 74.76%, 65.38% against Phomopsis adianticola and Magnaporthe oryzae in vitro activity. Furthermore, compounds 7l and 7t displayed obviously inhibition activities against Phomopsis adianticola compared to the hymexazol. Consequently, compounds 7l and 7t with six-membered alkane ring could be used as new motifs for further investigation.
- Wang, Shuangshuang,Bao, Longzhu,Wang, Wenda,Song, Di,Wang, Jingjing,Cao, Xiufang
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p. 257 - 266
(2018/08/04)
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- INHIBITORS OF TYPED 1 METHIONYL-TRNA SYNTHETASE AND METHODS OF USING THEM
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The present disclosure is generally directed to compositions useful in the inhibition of MetRS and methods for treating diseases that are ameliorated by the inhibition of MetRS.
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Paragraph 0016; 0117
(2019/01/11)
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- New process for synthesizing 1-hydroxycyclohexanecarboxylic acid and application
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The invention discloses a new process for synthesizing 1-hydroxycyclohexanecarboxylic acid and an application. During the synthesis of the 1-hydroxycyclohexanecarboxylic acid, an anhydrous system is adopted. According to the process, due to an anhydrous r
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Paragraph 0051; 0052
(2019/01/14)
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- Development of [18F]Maleimide-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging
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Dysregulation of glycogen synthase kinase-3β (GSK-3β) is implicated in the pathogenesis of neurodegenerative and psychiatric disorders. Thus, development of GSK-3β radiotracers for positron emission tomography (PET) imaging is of paramount importance, because such a noninvasive imaging technique would allow better understanding of the link between the activity of GSK-3β and central nervous system disorders in living organisms, and it would enable early detection of the enzyme’s aberrant activity. Herein, we report the synthesis and biological evaluation of a series of fluorine-substituted maleimide derivatives that are high-affinity GSK-3β inhibitors. Radiosynthesis of a potential GSK-3β tracer [18F]10a is achieved. Preliminary in vivo PET imaging studies in rodents show moderate brain uptake, although no saturable binding was observed in the brain. Further refinement of the lead scaffold to develop potent [18F]-labeled GSK-3 radiotracers for PET imaging of the central nervous system is warranted.
- Hu, Kongzhen,Patnaik, Debasis,Collier, Thomas Lee,Lee, Katarzyna N.,Gao, Han,Swoyer, Matthew R.,Rotstein, Benjamin H.,Krishnan, Hema S.,Liang, Steven H.,Wang, Jin,Yan, Zhiqiang,Hooker, Jacob M.,Vasdev, Neil,Haggarty, Stephen J.,Ngai, Ming-Yu
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supporting information
p. 287 - 292
(2017/03/17)
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- Development of methionyl-trna synthetase inhibitors as antibiotics for gram-positive bacterial infections
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Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of 1.3 g/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.
- Faghih, Omeed,Zhang, Zhongsheng,Ranade, Ranae M.,Gillespie, J. Robert,Creason, Sharon A.,Huang, Wenlin,Shibata, Sayaka,Barros-álvarez, Ximena,Verlinde, Christophe L. M. J.,Hol, Wim G. J.,Fan, Erkang,Buckner, Frederick S.
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supporting information
(2017/11/04)
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- ARYLOXYACETYLINDOLES AND ANALOGS AS ANTIBIOTIC TOLERANCE INHIBITORS
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The disclosure provides compounds and pharmaceutical compositions of aryloxyacetylindoles compounds and analogs useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds of general Formula (I) (I) or a pharmaceutically acceptable salt or prodrug thereof. Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa. Methods of treating bacterial infections in a subject, including Pseudomonas aeruginosa infections, are also provided by the disclosure.
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Paragraph 0709-0710
(2016/08/10)
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- Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity
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Recent analyses have highlighted the promotion of cancer migration and invasion, mediated through HDAC via MMP-2 and MMP-9. Since both class 1 HDACs and MMP-2/9 are involved in the migration and invasion of cancer, an attempt has been taken to design dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping and molecular docking approaches. The designed molecules were synthesized and showed a range of inhibitory activity against different MMP subtypes. Most of these designed compounds were selective towards MMP-2 but less potent against anti-targets like MMP-8, -12, etc. The highly active MMP-2 inhibitors were also found to be active towards HDAC-8 but less potent against other class 1 HDACs (HDAC-1 and -2). Molecular dynamics simulations revealed that the designed compounds may be acting through a distinct mechanism of action in the 'acetate ion channel' of HDAC-8. Some potent dual MMP-2/HDAC-8 inhibitors were further explored for in vitro cellular assays against human lung carcinoma cell line A549. These analyses revealed that some of these dual inhibitors have considerable anti-migratory and anti-invasive properties. The work may help to obtain some useful dual inhibitors.
- Halder, Amit K.,Mallick, Sumana,Shikha, Deep,Saha, Achintya,Saha, Krishna D.,Jha, Tarun
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p. 72373 - 72386
(2015/09/08)
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- New Pyrazolecarboxylic compd., its manufacturing method and pest control agents
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PROBLEM TO BE SOLVED: To provide a new pyrazole compound capable of showing excellent biological activity to not only spider mites but also Nematoda. SOLUTION: It is found that a new pyrazole compound having a nitrogen-containing hetero ring in a first position of a pyrazole ring and a sulfonate group in a fifth position shows excellent biological activity to not only the spider mites but also the Nematoda. COPYRIGHT: (C)2012,JPOandINPIT
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Paragraph 0125; 0126; 0127
(2018/05/03)
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- Synthesis, antimycobacterial, antiviral, antimicrobial activity and QSAR studies of N2-acyl isonicotinic acid hydrazide derivatives
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A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N′- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N 2 -tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides.
- Judge, Vikramjeet,Narasimhan, Balasubramanian,Ahuja, Munish,Sriram, Dharmarajan,Yogeeswari, Perumal,De Clercq, Erik,Pannecouque, Christophe,Balzarini, Jan
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- The first synthesis of [11C]SB-216763, a new potential PET agent for imaging of glycogen synthase kinase-3 (GSK-3)
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SB-216763 is a novel, potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor with an IC50 value of 34 nM. [11C]SB- 216763 (3-(2,4-dichlorophenyl)-4-(1-[11C]methyl-1H-indol-3-yl)-1H- pyrrole-2,5-dione), a new potential PET agent for imaging of GSK-3, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-555 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled maleic anhydride intermediate followed by the conversion to maleimide.
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
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experimental part
p. 245 - 249
(2011/02/27)
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- Synthesis of (2-chlorophenyl)(phenyl)methanones and 2-(2-chlorophenyl)-1- phenylethanones by Friedel-Crafts acylation of 2-chlorobenzoic acids and 2-(2-chlorophenyl)acetic acids using microwave heating
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Several 2-(2-chlorophenyl)-1-phenylethanones and (2-chlorophenyl)(phenyl) methanones were prepared by the Friedel-Crafts acylation reaction of 2-(2-chlorophenyl) acetic acids and 2-chlorocarboxylic acids, respectively, in the presence of cyanuric chloride, pyridine, and AlCl3 or FeCl 3 using microwave heating. The yields of the ketones were significantly higher than those obtained using conventional heating. In addition, similar reactions carried out with the less inexpensive and less toxic FeCl3 gave titled ketones in comparable yields. Interestingly, the FeCl3 catalyzed reactions gave pure ketones (no chromatographic purification required), whereas the AlCl3 catalyzed reaction gave impure product that required chromatographic purification.
- Mahdi, Jasia,Ankati, Haribabu,Gregory, Jill,Tenner, Brian,Biehl, Edward R.
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experimental part
p. 2594 - 2596
(2011/06/21)
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- Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents
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InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target for the development of novel drugs against tuberculosis. We exploited copper-catalyzed [3+2] cycloaddition between alkynes and different azides to afford 1,4-disubstituted triazole or α-ketotriazole derivatives. Several compounds bearing a lipophilic chain mimicking the substrate were able to inhibit InhA. Among them, 1-dodecyl-4-phenethyl-1H-1,2,3-triazole displayed a minimum inhibitory concentration inferior to 2 μg/mL against Mycobacterium tuberculosis H37Rv.
- Menendez, Christophe,Gau, Sylvain,Lherbet, Christian,Rodriguez, Frédéric,Inard, Cyril,Pasca, Maria Rosalia,Baltas, Michel
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scheme or table
p. 5524 - 5531
(2011/12/15)
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- Structural diversity-guided convenient construction of functionalized polysubstituted butenolides and lactam derivatives
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A molecular diversity-oriented convenient access to multi-substituted butenolides and lactam scaffolds via four different methods from various phenylacetic acid derivatives is described. The target molecules have been identified on the basis of analytical spectra data, and are useful synthons in the fields of medicine and agrochemicals.
- Ke, Shaoyong,Zhang, Ya-Ni,Shu, Wenming,Zhang, Zhigang,Shi, Liqiao,Liang, Ying,Wang, Kaimei,Yang, Ziwen
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experimental part
p. 1071 - 1079
(2012/03/12)
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- HERBICIDAL COMPOUNDS
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The present invention relates to a method of controlling plants or inhibiting plant growth which comprises applying to the plants or to the locus thereof a herbicidally effective amount of a compound of formula (I): wherein A1, A2, A3, A4, R3, R4 and R5 are as defined in claim 1; or a salt or N-oxide thereof. Furthermore, the present invention relates to processes for preparing compounds of formula (I), to intermediates used in the preparation of compounds of formula (I), to herbicidal compositions comprising compounds of formula (I) and to certain novel pyridopyridines, pyridodiazines and pyridotriazines.
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Page/Page column 46
(2009/08/16)
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- Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives
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Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D1-like and/or D2/
- El Aouad, Noureddine,Berenguer, Inmaculada,Romero, Vanessa,Marin, Paloma,Serrano, Angel,Andujar, Sebastian,Suvire, Fernando,Bermejo, Almudena,Ivorra, M. Dolores,Enriz, Ricardo D.,Cabedo, Nuria,Cortes, Diego
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experimental part
p. 4616 - 4621
(2009/12/26)
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- PHENOXYACETIC ACID DERIVATIVES USEFUL FOR TREATING RESPIRATORY DISEASES
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The invention relates to substituted phenoxyacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.Formula (I)
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Page/Page column 95
(2008/06/13)
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- DRUG FOR NERVE REGENERATION
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An object of the present invention is to provide a nerve regenerating drug, an agent for the promotion of neuropoiesis of a neural stem cell, a neuron obtained by culturing a neural stem cell in the presence of the agent for the promotion of neuropoiesis,
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Page/Page column 26
(2011/04/19)
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- Discovering novel chemical inhibitors of human cyclophilin A: Virtual screening, synthesis, and bioassay
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Cyclophilin A (CypA) is a member of cyclophilins, a family of the highly homologous peptidyl prolyl cis-trans isomerases (PPIases), which can bind to cyclosporin A (CsA). CypA plays critical roles in various biological processes, including protein folding, assembly, transportation, regulation of neuron growth, and HIV replication. The discovery of CypA inhibitor is now of a great special interest in the treatment of immunological disorders. In this study, a series of novel small molecular CypA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. The SPECS_1 database containing 85,000 small molecular compounds was searched by virtual screening against the crystal structure of human CypA. After SPR-based binding affinity assay, 15 compounds were found to show binding affinities to CypA at submicro-molar or micro-molar level (compounds 1-15). Seven compounds were selected as the starting point for the further structure modification in considering binding activity, synthesis difficulty, and structure similarity. We thus synthesized 40 new small molecular compounds (1-6, 15, 16a-q, 17a-d, and 18a-l), and four of which (compounds 16b, 16h, 16k, and 18g) showed high CypA PPIase inhibition activities with IC50s of 2.5-6.2 μM. Pharmacological assay indicated that these four compounds demonstrated somewhat inhibition activities against the proliferation of spleen cells.
- Li, Jian,Chen, Jing,Gui, Chunshan,Zhang, Li,Qin, Yu,Xu, Qiang,Zhang, Jian,Liu, Hong,Shen, Xu,Jiang, Hualiang
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p. 2209 - 2224
(2007/10/03)
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- ARYLALKANOIC ACID DERIVATIVE
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A compound represented by the general formula (I): [wherein Ar represents an optionally substituted aromatic ring; Xa, Xc, Ya, Yc, Z1, and Z2 each represents a bond, O, S, -CO-, -CS-, -CR3(OR4)-, -NR5-, -SO-, -SO2-, -CONR6-, or -NR6CO- (R3, R4, R5, and R6 are as defined in the description); Xb and Yb each represents a bond or a C1-20 divalent hydrocarbon group; R1 represents an optionally substituted hydrocarbon group; ring A represents an aromatic ring (other than benzimidazole) which may be further substituted; n is an integer of 1-8; ring B represents an aromatic ring (other than oxazole) which may be further substituted; W represents a C1-20 divalent saturated hydrocarbon group; and R2 represents -OR8 or -NR9R10 (R8, R9, and R10 are as defined in the description)] or a salt of the compound. It is useful as a preventive/therapeutic agent for diabetes, etc.
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Page/Page column 147
(2010/11/08)
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- Spirodiclofen and spiromesifen - Novel acaricidal and insecticidal tetronic acid derivatives with a new mode of action
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The broad spectrum acaricides spirodiclofen (BAJ2740, trade name: Envidor) and spiromesifen (BSN2060, trade name: Oberon) with an additional excellent activity against whiteflies, both belong to the new chemical class of tetronic acid derivatives discovered at Bayer CropScience during the 1990s. The discovery process starting from herbicidal PPO (protoporphyrinogen oxidase) chemistry, the synthetic routes leading to the products, and some insight into process development of central intermediates is given. Spirodiclofen and spiromesifen have a new mode of action (interference with lipid biosynthesis), show no cross-resistance to any resistant mite or whitefly field population and are therefore valuable tools for resistance management.
- Bretschneider, Thomas,Benet-Buchholz, Jordi,Fischer, Reiner,Nauen, Ralf
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p. 697 - 701
(2007/10/03)
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- Antiangiogenic and antitumor agents: Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases
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Several different classes of growth factor receptors containing tyrosine kinases (RTK) are directly or indirectly involved in angiogenesis. Inhibition of these RTKs has provided a new paradigm in the treatment of tumors by restricting their growth and metastasis. We have designed, synthesized and evaluated eleven novel 2-amino-4-(3-bromoanilino)-6-substituted benzyl pyrrolo[2,3-d]pyrimidines as the first in a series of RTK inhibitors. These analogues were synthesized from appropriate α-bromomethylbenzyl ketones by cyclocondensation with 2,6-diamino-4-pyrimidone to afford the 2-amino-4-oxo-6-substituted benzyl pyrrolo[2,3-d]pyrimidines. Chlorination of the 4-position followed by displacement with 3-bromoaniline afforded the target compounds. In some instances, the 2-amino moiety of the pyrrolo[2,3-d] pyrimidines was protected prior to the chlorination and displacement followed by deprotection. The compounds were evaluated as inhibitors of vascular endothelial growth factor receptors VEGFR-2 (Flk-1, KDR) and VEGFR-1 (Flt-1); epidermal growth factor receptor (EGFR); and platelet-derived growth factor receptor-β (PDGFR-β). Selected compounds were also evaluated against the growth of A431 cells (which overexpress EGFR) in culture and as inhibitors of angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay. In each evaluation, a known standard compound was used as a comparison. Of the 11 analogues, five were more potent or equipotent as compared to standard compounds against the growth factor receptors. Two analogues showed superior inhibition of A431 cells in culture compared to the standard compounds. Three analogues were equipotent with the standard compound in the CAM assay and four of the analogues were dual inhibitors of RTKs. The structure-activity relationship for inhibition of different RTKs was quite distinct and different, and for VEGFR-2 and EGFR diametrically opposite. The inhibitory data against the RTKs in this study demonstrates that variation of the substituent(s) in the benzyl ring of these 2-amino-4-anilino 6-benzyl pyrrolo[2,3-d]pyrimidines does indeed control both the potency and specificity of inhibitory activity against RTKs.
- Gangjee, Aleem,Yang, Jie,Ihnat, Michael A.,Kamat, Shekhar
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p. 5155 - 5170
(2007/10/03)
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- Synthesis, selective aldose reductase inhibitory profile and antihyperglycaemic potential of certain parabanic acid derivatives
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Synthesis and aldose reductase inhibitory profile of certain parabanic acid derivatives 1a-p is described. Also, the antihyperglycaemic potential of these compounds was studied. The most active inhibitors in this series were compounds 1 g, 1p, and 1o which showed inhibitory activity, 36.6, 90 and 91% respectively, at concentration 1 × 10-4. Their IC50 were 2 × 10-6, 7.5 × 10-8 and 5 × 10-8, respectively. Compound 1o exhibited pronounced antihyperglycaemic effect.
- Nabil Aboul-Enein,El-Azzounya,Maklad,Attia,Wiese
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p. 329 - 350
(2007/10/03)
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- Discovery of a series of nonpeptide small molecules that inhibit the binding of insulin-like growth factor (IGF) to IGF-binding proteins
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Insulin-like growth factors (IGF-I and II) play an important role in metabolic and mitogenic activities through stimulation of the IGF-I receptor on the cell surface. Although the concentration of IGF in blood and cerebrospinal fluid is quite high (>100 nM) this large pool of IGF is biologically inactive because of its association with six distinct binding proteins which form high-affinity complexes with IGF. Thus, inhibitors of IGF-binding proteins (IGFBPs), especially IGFBP-3, could potentially alter the distribution between the "free" and "bound" forms of IGF and thereby elevate biologically active IGF-I to exert a beneficial effect on those patients with diseases that respond to the application of exogenous IGF-I. Whereas IGF-I peptide variants which bind to IGFBPs but not the IGF-I receptor have been shown to be potent IGF/IGFBP inhibitors small molecule nonpeptide IGF/IGFBP inhibitors have the potential advantages of oral bioavailability and flexible dosing regimen. Here we report the discovery of several isoquinoline analogues, exemplified by 1 and 2, which bind IGFBP-3 as well as other IGFBPs at low nanomolar concentrations. More importantly, both compounds were shown to be able to release biologically active IGF-I from the IGF-I/IGFBP-3 complex. These results point to the feasibility of developing orally active therapeutics to treat IGF-responsive diseases by optimization of the lead molecules 1 and 2.
- Chen,Zhu,Liu,Lu,Xie,Ling
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p. 4001 - 4010
(2007/10/03)
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- THE PRODUCTION OF 2,4-DICHLOROPHENACYL CHLORIDE
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The acylation of a mixture of dichlorobenzene isomers by chloroacetyl chloride in the presence of anhydrous aluminum chloride leads to the selective formation of 2,4-dichlorophenacyl chloride.
- Rekhter, M. A.,Reinbol'd, A. I.,Krimer, M. Z.
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p. 1152 - 1153
(2007/10/02)
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