- FePd alloy nanoparticles assembled on reduced graphene oxide as a catalyst for selective transfer hydrogenation of nitroarenes to anilines using ammonia borane as a hydrogen source
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Addressed herein is a facile protocol for the synthesis and assembly of FePd alloy nanoparticles (NPs) on reduced graphene oxide (rGO) to catalyze transfer hydrogenation of nitroarenes to anilines under ambient conditions. 3.5 nm FePd NPs were synthesized by using a surfactant-assisted co-reduction method that allowed NP composition control. FePd NPs were then assembled on rGO via a liquid-phase self-assembly method and studied as catalysts to promote hydrogen transfer from ammonia borane (AB) to numerous nitroarenes in aqueous methanol solutions at room temperature. Among three different rGO-FePd, the commercial C-Pd and rGO-Pd catalysts tested, rGO-Fe48Pd52 showed the highest efficiency in converting nitroarenes to anilines, achieving >90% yields within 10-20 min of reactions. Our work demonstrates an efficient and selective approach to transfer hydrogenation of nitroarenes to anilines.
- Metin, ?nder,Mendoza-Garcia, Adriana,Dalmizrak, Di?dem,Gültekin, Mehmet Serdar,Sun, Shouheng
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Read Online
- Serendipitous discovery of potent human head and neck squamous cell carcinoma anti-cancer molecules: A fortunate failure of a rational molecular design
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Histone deacetylase inhibitors (HDACis) play an important role as valuable drugs targeted to cancer therapy: several HDACis are currently being tested in clinical trials. Two new potential HDACis 1a and 1d, characterized by the presence of a biphenyl-4-sulfonamide group as a connection unit between the N-{4-[(E)-(2-formylhydrazinylidene)methyl]-3-hydroxyphenyl} and the 2-hydroxy-N-(trifluoroacetyl)benzamide moiety, respectively, as two zinc-binding group (ZBG), have been designed, synthesized and tested for their biological activity. Surprisingly, compounds 1a and 12, this last exclusively obtained in place of 1d, exhibited a very low HDAC inhibitory activity. A serendipitous assay of these two compounds, conducted on three chemoresistant cell lines of head and neck squamous cell carcinoma (HNSCC), showed their antiproliferative activity at low nanomolar concentrations, better than cisplatin. In vitro, biological assays indicated that compounds 1a and 12 are able to increase acetylation of histone H3 and to interfere with the PI3K/Akt/mTOR pathway by inducing the accumulation of PTEN protein.
- Zagni, Chiara,Pistarà, Venerando,Oliveira, Luciana A.,Castilho, Rogerio M.,Romeo, Giovanni,Chiacchio, Ugo,Rescifina, Antonio
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- Synthesis, colon-targeted studies and pharmacological evaluation of an anti-ulcerative colitis drug 4-Aminosalicylic acid-β-O-glucoside
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A glycoside prodrug of 4-aminosalicylic acid (4-ASA) with d-glucose was synthesized for targeted drug delivery to inflammatory bowel. The in vitro assessment of 4-aminosalicylic acid-β-O-glucoside (4-ASA-Glu) as a colon-specific prodrug was studied using colitis rat with the healthy one as control. The stability studies in aqueous buffers (pH 1.2, 6.8 and 7.4) indicated that 4-ASA-Glu was stable over a period of 12 h. The incubation of 4-ASA-Glu with cecal or colonic contents of healthy rats at 37 °C released 4-ASA in 77 or 80% of the dose in 12 h, respectively. The amount of 4-ASA liberated from the incubation of 4-ASA-Glu in cecal or colonic contents of colitis rats at 37 °C was 69 or 79% in 12 h respectively, while less than 9% 4-ASA was detected from the incubation of 4-ASA-Glu with the homogenates of stomach or small intestine. The curative effect of 4-ASA-Glu was evaluated in 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) induced experimental colitis model in male Sprague-Dawley (SD) rats. It was found that 4-ASA-Glu possess significantly ameliorate effect than sulfasalazine, oral 4- and 5-aminosalicylic acid.
- Li, Feifei,Wu, Guoli,Zheng, Huixia,Wang, Li,Zhao, Zhengbao
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- Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS)
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Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
- Aldrich, Courtney C.,Baughn, Anthony D.,Boshoff, Helena I. M.,Dartois, Veronique,Hegde, Pooja V.,Howe, Michael D.,Jia, Ziyi,Pan, Yan,Remache, Brianna,Sharma, Sachin,Zimmerman, Matthew D.
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- New dual ATP-competitive inhibitors of bacterial DNA gyrase and topoisomerase IV active against ESKAPE pathogens
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The rise in multidrug-resistant bacteria defines the need for identification of new antibacterial agents that are less prone to resistance acquisition. Compounds that simultaneously inhibit multiple bacterial targets are more likely to suppress the evolution of target-based resistance than monotargeting compounds. The structurally similar ATP binding sites of DNA gyrase and topoisomerase Ⅳ offer an opportunity to accomplish this goal. Here we present the design and structure-activity relationship analysis of balanced, low nanomolar inhibitors of bacterial DNA gyrase and topoisomerase IV that show potent antibacterial activities against the ESKAPE pathogens. For inhibitor 31c, a crystal structure in complex with Staphylococcus aureus DNA gyrase B was obtained that confirms the mode of action of these compounds. The best inhibitor, 31h, does not show any in vitro cytotoxicity and has excellent potency against Gram-positive (MICs: range, 0.0078–0.0625 μg/mL) and Gram-negative pathogens (MICs: range, 1–2 μg/mL). Furthermore, 31h inhibits GyrB mutants that can develop resistance to other drugs. Based on these data, we expect that structural derivatives of 31h will represent a step toward clinically efficacious multitargeting antimicrobials that are not impacted by existing antimicrobial resistance.
- Durcik, Martina,Nyerges, ákos,Skok, ?iga,Skledar, Darja Gramec,Trontelj, Jurij,Zidar, Nace,Ila?, Janez,Zega, Anamarija,Cruz, Cristina D.,Tammela, P?ivi,Welin, Martin,Kimbung, Yengo R.,Focht, Dorota,Benek, Ond?ej,Révész, Tamás,Draskovits, Gábor,Szili, Petra éva,Daruka, Lejla,Pál, Csaba,Kikelj, Danijel,Ma?i?, Lucija Peterlin,Toma?i?, Tihomir
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- Synthesis and biological evaluation of salicylic acid analogues of celecoxib as a new class of selective cyclooxygenase-1 inhibitor
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A series of salicylic acid analogues of celecoxib where the phenylsulfonamide moiety in the structure of celecoxib is replaced by salicylic acid moiety was synthesized and tested for in vitro cyclooxygenase (COX)-1 and COX-2 enzyme inhibition. Among the series, 5-substituted-2-hydroxy-benzoic acid analogues (7a–7h) generally showed better inhibitory activities on both enzymes than 4-substituted-2-hydroxy-ben-zoic acid analogues (12a–12h). In particular, the chloro analogue 7f which had the highest inhibitory effect (IC50=0.0057μM) to COX-1 with excellent COX-1 selectivity (SI=768) can be classified as a new potent and selective COX-1 inhibitor. The high inhibitory potency of 7f was rationalized through the docking simulation of this analogue in the active site of COX-1 enzyme.
- Yoon, Sung-Hwa,Cho, Duk-Yeon,Choi, Seoung-Ryoung,Lee, Joo-Young,Choi, Dong-Kug,Kim, Eunha,Park, Ju-Young
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p. 1230 - 1238
(2021/09/06)
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- Fluoroquinolone derivative of p-aminosalicylic acid as well as intermediate, preparation method and application of fluoroquinolone derivative
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The invention discloses a fluoroquinolone derivative of p-aminosalicylic acid as well as an intermediate, a preparation method and application of the fluoroquinolone derivative, and belongs to the technical field of drug synthesis. The structural formula of the fluoroquinolone derivative of p-aminosalicylic acid is shown in the specification. An in-vitro antibacterial activity determination resultshows that the target compound has good inhibition activity on bacteria as a whole; most compounds have good antibacterial activity on pichia pastoris, and some compounds have activity even strongerthan that of positive control drugs; the inhibitory activity of the two intermediates on mycobacterium smegmatis is higher than that of most positive control drugs; part of the target compounds have inhibitory activity on citrus germs. The fluoroquinolone derivative of p-aminosalicylic acid and the intermediate have potential application prospects in the fields of bacterium resistance, fungus resistance, tuberculosis resistance and citrus pathogen resistance.
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Paragraph 0051-0054
(2021/01/24)
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- P-aminosalicylic acid fluoroquinolone derivative as well as intermediate, preparation method and application thereof
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The invention discloses a p-aminosalicylic acid fluoroquinolone derivative and an intermediate, a preparation method and application thereof, and belongs to the technical field of drug synthesis. Thestructural formula of the p-aminosalicylic acid fluoroquinolone derivative is shown in the specification. In-vitro activity determination results show that part of fluoroquinolone aminosalicylate derivatives (compounds for short) and intermediates have inhibition effects on mycobacterium smegmatis; the compounds and intermediates have good inhibition activity on common pathogenic bacteria as a whole; most compounds and intermediates have better antibacterial activity on pichia pastoris as a whole; part of the compounds have good inhibitory activity on citrus canker pathogens. The p-aminosalicylic acid fluoroquinolone derivative and the intermediate thereof have potential application prospects in the fields of tuberculosis resistance, bacteria resistance, fungus resistance and citrus pathogen resistance.
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Paragraph 0053-0056
(2021/01/24)
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- NEW CLASS OF DNA GYRASE AND/OR TOPOISOMERASE IV INHIBITORS WITH ACTIVITY AGAINST GRAM-POSITIVE AND GRAM-NEGATIVE BACTERIA
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The present invention relates to compounds having a structure of general formula (I), processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in humans and warm-blooded animals.
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Page/Page column 56-57; 68
(2020/03/29)
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- Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics
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Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids—a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.
- Elgaher, Walid A. M.,Hamed, Mostafa M.,Baumann, Sascha,Herrmann, Jennifer,Siebenbürger, Lorenz,Krull, Jana,Cirnski, Katarina,Kirschning, Andreas,Br?nstrup, Mark,Müller, Rolf,Hartmann, Rolf W.
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p. 7219 - 7225
(2020/05/08)
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- Methyl 4-acetamido-2-butoxybenzoate derivatives as well as preparation method and application thereof
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The invention relates to methyl 4-acetamido-2-butoxybenzoate derivatives as well as a preparation method and application thereof, and belongs to the field of medicinal chemistry. The structural formula of the methyl 4-acetamido-2-butoxybenzoate derivatives is shown in the specification, wherein R1 is alkyl, substituted phenyl, heteroaromatic ring group or substituted styryl; and R2 is fatty aminoor benzylamino. The preparation method is simple and high in yield. Most compounds provided by the invention have good influenza virus neuraminidase inhibition activity.
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Paragraph 0007; 0020; 0021
(2020/08/03)
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- Preparation method of key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of 5-HT4 receptor stimulant
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The invention discloses a preparation method of a key intermediate 4-amino-5-halobenzofuran-7-carboxylic acid of a 1,5-HT4 receptor stimulant, belonging to the field of organic synthesis. According tothe preparation method, para-protected amino-o-hydroxybenzoic acid/hydroxybenzoate, a halogenating reagent and triethyl acetenyl silicon are used as main raw materials, and a three-step reaction is performed to obtain the 4-amino-5-halobenzofuran-7-carboxylic acid. The method has the advantages of simple process operation, short reaction steps, easy separation of the intermediate, total yield ofmore than 51%, usage cheap and easily available raw materials and greatly reduced production cost; and thus, the method has obvious competitive advantages.
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Paragraph 0076-0082
(2020/03/02)
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- para-aminosalicylic acid azole derivative as well as preparation method and application thereof
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The invention discloses a para-aminosalicylic acid azole derivative as well as a preparation method and application thereof, and belongs to the technical field of drug synthesis. The structural formula of the para-aminosalicylic acid azole derivative is shown in the specifications. An antibacterial activity determination result shows that the para-aminosalicylic acid azole derivative disclosed bythe invention has good inhibition activity on common pathogenic bacteria as a whole, and the antibacterial activity of part of molecules on pichia pastoris is stronger than or equal to that of a positive drug, fluconazole; all the molecules have good inhibitory activity on colletotrichum gloeosporioides, part of the molecules have the inhibitory activity equal to or higher than that of positive control prochloraz, and most of the molecules have a good inhibitory effect on citrus canker pathogens. An anti-tumor cell activity determination result shows that the para-aminosalicylic acid azole derivative disclosed by the invention has an inhibition effect on the three kinds of tumor cells. The para-aminosalicylic acid azole derivative disclosed by the invention has a potential application prospect in the fields of bacterium resistance, fungus resistance, citrus pathogen resistance and tumor resistance.
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Paragraph 0051-0054
(2020/12/15)
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- A New Series of Salicylic Acid Derivatives as Non-saccharide α-Glucosidase Inhibitors and Antioxidants
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In this study, a series of salicylic acid derivatives were designed and synthesized as novel non-saccharide α-glucosidase inhibitors. Biological evaluation indicated that when compared to acarbose, compounds T9, T10, and T32 exhibited a higher potency of α-glucosidase inhibitory activity with IC50 values of 0.15±0.01, 0.086±0.01 and 0.32±0.02mM, respectively. Evaluation of the inhibition kinetics indicated that T9, T10, T32, and acarbose interacted with α-glucosidase in a mixed non-competitive inhibitory manner. Moreover, T9, T10, and T32 statically quenched the fluorescence of α-glucosidase by formation of an inhibitor-α-glucosidase complex. The docking results showed that hydrogen bonds were generated between the test compounds and α-glucosidase. The antioxidant study revealed that compound T10 exhibited a higher antioxidant activity via scavenging 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH), thereby inhibiting lipid peroxidation and the total reduction capacity. In brief, the salicylic acid derivatives identified in this study were promising candidates for development as novel non-saccharide α-glucosidase inhibitors.
- Chen, Jiangang,Lu, Wenfang,Chen, Hao,Bian, Xiaoli,Yang, Guangde
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p. 231 - 246
(2019/02/19)
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- Synthesis and Evaluation of N-Phenylpyrrolamides as DNA Gyrase B Inhibitors
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ATP-competitive inhibitors of DNA gyrase and topoisomerase IV are among the most interesting classes of antibacterial drugs that are unrepresented in the antibacterial pipeline. We developed 32 new N-phenylpyrrolamides and evaluated them against DNA gyrase and topoisomerase IV from E. coli and Staphylococcus aureus. Antibacterial activities were studied against Gram-positive and Gram-negative bacterial strains. The most potent compound displayed an IC50 of 47 nm against E. coli DNA gyrase, and a minimum inhibitory concentration (MIC) of 12.5 μm against the Gram-positive Enterococcus faecalis. Some compounds displayed good antibacterial activities against an efflux-pump-deficient E. coli strain (MIC=6.25 μm) and against wild-type E. coli in the presence of efflux pump inhibitor PAβN (MIC=3.13 μm). Here we describe new findings regarding the structure–activity relationships of N-phenylpyrrolamide DNA gyrase B inhibitors and investigate the factors that are important for the antibacterial activity of this class of compounds.
- Durcik, Martina,Tammela, P?ivi,Baran?oková, Michaela,Toma?i?, Tihomir,Ila?, Janez,Kikelj, Danijel,Zidar, Nace
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supporting information
p. 186 - 198
(2018/02/06)
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- Preparation method of ethopabate
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The invention discloses a preparation method of ethopabate. Initially, para-aminosalicylic acid and p-toluene sulfonic acid are dissolved in methanol to form a mixed solution, the mixed solution is put in a reaction bottle, evenly stirred and heated, and a thermal insulation reaction is carried out; sodium acetate is added into a methyl p-aminosalicylate reaction liquid, the pH and temperature ofthe reaction liquid are controlled, acetylase is added, and a reaction is carried out to obtain methyl p-acetaminosalicylate; methyl p-acetaminosalicylate is added into acetone, heating is carried out, diethyl sulfate is added dropwisely, and after adding dropwisely is completed, a reaction is carried out to obtain ethopabate. The method has the advantages that industrial production can be achieved, resource conservation and environmental protection can be achieved, the cost can be better saved, the product quality is stable, the yield is high, and the method is suitable for large-scale industrial stable production.
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Paragraph 0022; 0023
(2018/04/01)
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- Synthetic method for prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid
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The invention belongs to the technical field of medicines, and relates to a synthetic method for a prucalopride succinate intermediate 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid. The final product 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid is obtained by using p-aminosalicylic acid as a starting raw material, successively performing esterification, acylation, and twice halogenation to obtain 4-acetylamino-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester, then performing substitution reaction on 1,2-dibromoethane and the 4-acetylamino-3-bromo-5-chloro-2-hydroxybenzoic acid methyl ester to obtain 4-acetylamino-3-bromo-2-(2-bromoethoxy)-5-chlorobenzoic acid methyl ester, and successively performing cyclization and hydrolyzation. According to the invention, the raw materials are easy to get, the operation is simple and mild, the production period is short, the purity is high, the safety is good, the costs are low, and the synthetic method is suitable for industrialized production.
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Paragraph 0039; 0040
(2017/12/06)
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- SMALL MOLECULE INHIBITORS OF THE MCL-1 ONCOPROTEIN AND USES THEREOF
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Compounds that inhibit Myeloid Cell Leukemia-1 (Mcl-1) oncoprotein, and methods of using the same, are provided for treating disease.
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Paragraph 00364-00365
(2017/02/09)
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- Graphene-Supported NiPd Alloy Nanoparticles for Effective Catalysis of Tandem Dehydrogenation of Ammonia Borane and Hydrogenation of Nitro/Nitrile Compounds
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Monodisperse NiPd alloy nanoparticles (NPs) are synthesized and assembled on graphene (G) or other support to provide clean, efficient catalysis of tandem reactions—dehydrogenation of ammonia borane (AB) and hydrogenation of R—NO2 and/or R—CN to R—NH2. The tandem reactions proceed quickly and with high efficiency in aqueous methanol solutions at room temperature, and the supported catalyst is readily recovered for re-use, providing a simple, efficient and ‘green’ route to the preparation of many common pharmaceutical, dye or other chemical products. NiPd alloy NPs of 3.4 nanometer size were prepared by co-reduction of nickel(II) acetate and palladium(II) acetlyacetonate by borane-tert-butylamine in oleylamine and deposited on G via a solution phase self-assembly process. The G-NiPd showed composition-dependent catalysis on the tandem reaction with G-Ni30Pd70 being the most active. A variety of R—NO2 and/or R—CN derivatives (R alkyl or aryl) were reduced selectively into R—NH2 via G-Ni30Pd70 catalyzed tandem reaction in short (5-30 minute) reaction times with conversion yields reaching up to 100%, demonstrating a new approach to G-NiPd-catalyzed dehydrogenation of AB and hydrogenation of R—NO2 and R—CN. The G-NiPd NP catalyst is efficient and is reusable; thus the reaction can be performed in an environment-friendly process with short reaction times and high yields.
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Paragraph 0022
(2016/10/17)
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- Synthesis and evaluation of novel serotonin 4 receptor radiotracers for single photon emission computed tomography
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Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [125I]-SB207710.
- Lalut, Julien,Tournier, Benjamin B.,Cailly, Thomas,Lecoutey, Cédric,Corvaisier, Sophie,Davis, Audrey,Ballandonne, Céline,Since, Marc,Millet, Philippe,Fabis, Frédéric,Dallemagne, Patrick,Rochais, Christophe
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- AMIDE COMPOUNDS AS 5-HT4 RECEPTOR AGONISTS
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The present invention relates to compounds of formula (I), including their stereoisomers and pharmaceutically acceptable salts. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to 5-hydroxytryptamine 4 (5-HT4) receptor.
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Page/Page column 25
(2016/09/22)
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- Dual-Reactable Fluorescent Probes for Highly Selective and Sensitive Detection of Biological H2S
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Hydrogen sulfide (H2S) is an important endogenous signaling molecule with a variety of biological functions. Development of fluorescent probes for highly selective and sensitive detection of H2S is necessary. We show here that dual-reactable fluorescent H2S probes could react with higher selectivity than single-reactable probes. One of the dual-reactable probes gives more than 4000-fold turn-on response when reacting with H2S, the largest response among fluorescent H2S probes reported thus far. In addition, the probe could be used for high-throughput enzymatic assays and for the detection of Cys-induced H2S in cells and in zebrafish. These dual-reactable probes hold potential for highly selective and sensitive detection of H2S in biological systems. Two heads are better than one: Fluorescent probes with two types of reactive heads (R1 and R2) for H2S can lead to a higher selectivity than that of single-reactable probes (See Figure). The probe was used for highly selective and sensitive detection of biological H2S.
- Wei, Chao,Wang, Runyu,Zhang, Changyu,Xu, Guoce,Li, Yanyan,Zhang, Qiang-Zhe,Li, Lu-Yuan,Yi, Long,Xi, Zhen
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supporting information
p. 1376 - 1381
(2016/05/19)
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- 2,4-Pyrimidinediamine Compounds and Their Uses
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The present invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.
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Paragraph 1017
(2015/11/10)
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- 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOL DERIVATIVES AS PHOSPHODIESTERASE INHIBITORS
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Compounds of formula (I) described herein are inhibitors of the phosphodiesterase 4 (PDE4) enzyme and are useful for the prevention and/or treatment of an allergic disease state or a disease of the respiratory tract characterized by airway obstruction.
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- HETEROARYL COMPOUNDS AS 5-HT4 RECEPTOR LIGANDS
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The present invention relates to novel compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptors.
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Paragraph 0091-0094
(2014/07/08)
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- Tandem dehydrogenation of ammonia borane and hydrogenation of nitro/nitrile compounds catalyzed by graphene-supported NiPd alloy nanoparticles
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We report a facile synthesis of monodisperse NiPd alloy nanoparticles (NPs) and their assembly on graphene (G) to catalyze the tandem dehydrogenation of ammonia borane (AB) and hydrogenation of R-NO2 and/or R-CN to R-NH2 in aqueous methanol solutions at room temperature. The 3.4 nm NiPd alloy NPs were prepared by coreduction of nickel(II) acetate and palladium(II) acetlyacetonate by borane-tert-butylamine in oleylamine and deposition on G via a solution phase self-assembly process. G-NiPd showed composition-dependent catalysis on the tandem reaction with G-Ni 30Pd70 being the most active. A variety of R-NO 2 and/or R-CN derivatives were reduced selectively into R-NH 2 via G-Ni30Pd70 catalyzed tandem reaction in 5-30 min reaction time with the conversion yields reaching up to 100%. Our study demonstrates a new approach to G-NiPd-catalyzed dehydrogenation of AB and hydrogenation of R-NO2 and R-CN. The G-NiPd NP catalyst is efficient and reusable, and the reaction can be performed in an environment-friendly process with short reaction times and high yields.
- Goeksu, Haydar,Ho, Sally Fae,Metin, Oender,Korkmaz, Katip,Mendoza Garcia, Adriana,Gueltekin, Mehmet Serdar,Sun, Shouheng
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p. 1777 - 1782
(2014/06/24)
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- HETEROARYL COMPOUNDS AS 5-HT4 RECEPTOR LIGANDS
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The present invention relates to novel compounds of formula (I), and their pharmaceutically acceptable salts and compositions containing them. The present invention also relates to a process for the preparation of above said novel compounds, and their pharmaceutically acceptable salts. The compounds of formula (I) are useful in the treatment of various disorders that are related to 5-HT4 receptors.
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Page/Page column 10; 11
(2013/04/10)
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- 4,5-Diamino-3-Halo-2-Hydroxybenzoic Acid Derivatives and Preparations Thereof
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Disclosed are 4,5-diamino-3-halo-2-hydroxybenzoic acid derivatives and manufactures thereof. The 4,5-diamino-3-halo-2-hydroxybenzoic acid derivatives are presented by formula (I): wherein R1 group is H, CH3, or C2H5; R2 group is H, or Br; R3 group is CH3, or C3H7; and R4 group is H, or C(═NH)—NH2. 4,5-diamino-3-halo-2-hydroxybenzoic acid derivatives provided here were non-toxic to MDCK cells, particularly compounds 6a, 6b, 6c, 6e, 6f, 7a, 7b and 8 had better anti-H1N1 activity. In the future, these compounds can be used to focus on viral neuraminidases as targets to develop effective anti-influenza drugs.
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Page/Page column 9
(2012/05/04)
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- Syntheses of mycobactin analogs as potent and selective inhibitors of Mycobacterium tuberculosis
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Three analogs of mycobactin T, the siderophore secreted by Mycobacterium tuberculosis (Mtb) were synthesized and screened for their antibiotic activity against Mtb H37Rv and a broad panel of Gram-positive and Gram-negative bacteria. The synthetic mycobactins were potent (MIC90 0.02-0.88 μM in 7H12 media) and selective Mtb inhibitors, with no inhibitory activity observed against any other of the microorganisms tested. The maleimide-containing analog 40 represents a versatile platform for the development of mycobactin-drug conjugates, as well as other applications.
- Juárez-Hernández, Raúl E.,Franzblau, Scott G.,Miller, Marvin J.
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supporting information
p. 7584 - 7593
(2012/10/29)
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- TYROSINE PHOSPHATASE INHIBITORS AND USES THEREOF TO MODULATE THE ACTIVITY OF LYP
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A variety of benzofurans and indole derivatives some with an acetyl linker are disclosed herein. These compounds are not highly charged at physiological pH and have good bioavailability characteristics. These compounds exhibit selective or at least preferential affinity for the active sites of various sub-sets of protein tyrosine phosphatases. The lymphoid- specific tyrosine phosphatase (Lyp) has received enormous attention because of the finding that a single- nucleotide polymorphism (SNP) in the gene (PTPN22) encoding Lyp is associated with several autoimmune diseases, including type I diabetes. Many of these compounds and pharmaceutically acceptable salts thereof are novel therapeutic compounds useful for the treatment of various diseases including a number of autoimmune diseases.
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Page/Page column 88; 89; 97
(2012/11/13)
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- Development of a fluorescent chelating ligand for scandium ion having a Schiff base moiety
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A fluorescent ligand, 1-(2-hydroxy-3-methoxybenzaldehyde)-4- aminosalicylhydrazone (HMB-ASH), was newly designed and synthesized, and its fluorescence characteristics for metal ions were investigated in the pH range 3.0-10.5 (at a difference of 0.5 for each metal). After testing 31 different metal ions, it was found that HMB-ASH was able to emit fluorescence intensely at 512 nm with an excitation wavelength of 353 nm in the presence of Sc 3+, one of the rare earth metals, at pH values around 3.5 and 8.0. The other metal ions hardly showed fluorescence with HMB-ASH. The fluorescence was more intense at pH 8.0, and the detection limit of Sc3+ in a buffer solution (pH 8.0) was approximately 18.8 nmol L-1 (0.85 ppb).
- Yamada, Hiroshi,Kojo, Masahito,Nakahara, Tomomi,Murakami, Kumi,Kakima, Takashi,Ichiba, Hideaki,Yajima, Takehiko,Fukushima, Takeshi
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experimental part
p. 72 - 77
(2012/04/23)
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- Synthesis and biological evaluation of berberine derivatives as IBS modulator
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Irritable bowel syndrome is the most common functional gastrointestinal disorder characterized by chronic abdominal pain or discomfort in association with a change in bowel habit. 5-HT receptor modulators have been developed as IBS therapeutic agents and proved to be effective in the treatment of the disease. In this letter, 12 berberine derivatives were designed and synthesized as 5-HT receptor modulators. Preliminary biological tests suggested that the new compounds exhibited promising activity for IBS therapy.
- Deng, Xin,Zhao, Xinxin,Han, Jing,Wang, Jingjie,Huang, Wenlong,Qian, Hai,Ge, Liang
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scheme or table
p. 489 - 493
(2012/08/29)
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- Syntheses of 1,2,3-triazolyl salicylamides with inhibitory activity on lipopolysaccharide-induced nitric oxide production
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A 28-membered 1,2,3-triazolyl salicylamide library was synthesized via a Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and evaluated for their abilities to inhibit NO production in LPS-activated RAW264.7 macrophage cells. Among 28 analogues, 29g showed a significant inhibitory activity (IC 50 = 12.8 μM). The inhibitory effects of 29g on LPS-mediated NO production in macrophage cells appeared to be associated with the suppression of iNOS expression.
- Yoon, Jieun,Cho, Lan,Lee, Sang Kook,Ryu, Jae-Sang
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supporting information; experimental part
p. 1953 - 1957
(2011/05/02)
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- Salicylic acid based small molecule inhibitor for the oncogenic src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2)
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The Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) plays a pivotal role in growth factor and cytokine signaling. Gain-of-function SHP2 mutations are associated with Noonan syndrome, various kinds of leukemias, and solid tumors. Thus, there is considerable interest in SHP2 as a potential target for anticancer and antileukemia therapy. We report a salicylic acid based combinatorial library approach aimed at binding both active site and unique nearby subpockets for enhanced affinity and selectivity. Screening of the library led to the identification of a SHP2 inhibitor II-B08 (compound 9) with highly efficacious cellular activity. Compound 9 blocks growth factor stimulated ERK1/2 activation and hematopoietic progenitor proliferation, providing supporting evidence that chemical inhibition of SHP2 may be therapeutically useful for anticancer and antileukemia treatment. X-ray crystallographic analysis of the structure of SHP2 in complex with 9 reveals molecular determinants that can be exploited for the acquisition of more potent and selective SHP2 inhibitors.
- Zhang, Xian,He, Yantao,Liu, Sijiu,Yu, Zhihong,Jiang, Zhong-Xing,Yang, Zhenyun,Dong, Yuanshu,Nabinger, Sarah C.,Wu, Li,Gunawan, Andrea M.,Wang, Lina,Chan, Rebecca J.,Zhang, Zhong-Yin
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experimental part
p. 2482 - 2493
(2010/09/03)
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- Investigation of Synthetic Routes to a Key Benzopyran Intermediate of a 5HT4 Agonist
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The supply route to GlaxoSmithKline's 5HT4 receptor agonist 1 centred on the construction of key benzopyran fragment 2. Our attempts to define the final manufacturing route for this component are described through a series of disconnections. The systematic approach undertaken towards the construction of the benzopyran skeleton focused on cycli- sation strategies from appropriate precursors and evaluation of the performance of the key steps.
- Rassias, Geracimos,Stevenson, Neil G.,Curtis, Neil R.,Northall, John M.,Gray, Matthew,Prodger, Jeremy C.,Walker, Andrew J.
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experimental part
p. 92 - 98
(2010/04/28)
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- Salicylate-urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities
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We investigated N-adamantyl-N′-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such inhibitors are potential lead molecule for bioactive compounds acting in vivo.
- Kasagami, Takeo,Kim, In-Hae,Tsai, Hsing-Ju,Nishi, Kosuke,Hammock, Bruce D.,Morisseau, Christophe
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supporting information; experimental part
p. 1784 - 1789
(2009/12/03)
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- Synthesis and modeling of new benzofuranone histone deacetylase inhibitors that stimulate tumor suppressor gene expression
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New benzofuranones were synthesized and evaluated toward NCI-H661 non-small cell lung cancer cells. Benzamide derivatives possessed micromolar antiproliferative and histone deacetylase inhibitory activities and modulate histone H4 acetylation. Hydroxamic acids were found to be potent nanomolar antiproliferative agents and HDAC inhibitors. Computational analysis presented a rationale for the activities of the hydroxamate derivatives. Impact of the HDAC inhibition on the expression of E-cadherin and the SEMA3F tumor suppressor genes revealed new promising compounds for lung cancer treatments.
- Charrier, Cédric,Clarhaut, Jonathan,Gesson, Jean-Pierre,Estiu, Guillermina,Wiest, Olaf,Roche, Jo?lle,Bertrand, Philippe
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supporting information; experimental part
p. 3112 - 3115
(2010/02/28)
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- Design, synthesis, inhibitory activity, and SAR studies of hydrophobic p-aminosalicylic acid derivatives as neuraminidase inhibitors
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A series of hydrophobic p-aminosalicylic acid derivatives containing a lipophilic side chain at C-2 and an amino or guanidine at C-5 were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus (H3N2). All compounds were synthesized in good yields starting from commercially available p-aminosalicylic acid (PAS) using a suitable synthetic strategy. These compounds showed potent inhibitory activity against influenza A NA. Within this series, six compounds, 11, 12, 13e, 16e, 17c, and 18e, have the good potency (IC50 = 0.032-0.049 μM), which are compared to Oseltamivir (IC50 = 0.021 μM) and could be used as lead compounds in the future.
- Zhang, Jie,Wang, Qiang,Fang, Hao,Xu, Wenfang,Liu, Ailin,Du, Guanhua
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p. 3839 - 3847
(2008/09/21)
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- NOVEL COMPOUND
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The present invention relates to a novel benzofuran carboxamide derivative having pharmacological activity, to processes for its preparation, to compositions containing it and to its use in the treatment of diseases treatable by 5-HT4 agonism.
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Page/Page column 12; 26-27
(2008/06/13)
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- Utility of Japp-Klingemann reaction for the preparation of 5-carboxy-6-chloroindole via Fischer indole protocol
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5-Carboxy-6-chloroindole, a precursor for p38 kinase inhibitor, was prepared from 4-amino-2-chloro-3-iodobenzoicacid by following the Japp-Klingemann synthetic approach. The structures of the key intermediates were also confirmed by X-ray analyses. Computational analysis was helpful in understanding the importance of the substituents at the cyclization step of the synthesis.
- Chen, Yihui,Shibata, Masayuki,Rajeswaran, Manju,Srikrishnan, Thamarapu,Dugar, Sundeep,Pandey, Ravindra K.
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p. 2353 - 2356
(2007/10/03)
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- Synthesis, structure-activity relationship, and p210bcr-abl protein tyrosine kinase activity of novel AG 957 analogs
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A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity relationship associated with the carboxylic acid, phenol ring, and linker modifications are discussed. We have demonstrated that the 1,4-hydroquinone moiety is essential for activity and that sterically hindered esters contribute to enhanced in vivo efficacy. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity, concordant with the original lead compound AG 957. Currently, adaphostin is undergoing preclinical toxicology studies.
- Kaur, Gurmeet,Narayanan, Ven L.,Risbood, Prabhakar A.,Hollingshead, Melinda G.,Stinson, Sherman F.,Varma, Ravi K.,Sausville, Edward A.
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p. 1749 - 1761
(2007/10/03)
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- Bridged bicyclic amine derivatives useful as CCR-3 receptor antagonists
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Compounds having the formula (I), Ar—(F)(E)-(CR3R4)—(CHR5)m-(T)-(Q)-Ar1, are useful as CCR-3 receptor antagonists, wherein T is a bridged heterocyclyl group having one N atom and a bridge of one to two bridgehead carbon atoms; Ar and Ar1 are aryl or heteroaryl; F is alkylene, alkenylene, or a bond; E is —C(═O)N(R10)—, —SO2N(R10)—, —N(R11)C(═O)N(R10O)—, —N(R11)SO2N(R10)—, —N(R11)C(═S)N(R10)—, —N(R11)C(═O)—, —N(R11)SO2—, —N(R12)C(═O)CH(R13)—, or CH(R13)C(═O)N(R12)—; Q is —C(═O)— or C1-2alkylene; and R3, R4, R5, R9, R10, R11, R12, and R13 are defined as set forth in the specification.
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Page/Page column 8; 9
(2010/02/08)
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- Design and synthesis of novel CCR3 antagonists
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As part of our investigation into the development of potent CCR3 antagonists, a series of piperidine analogues was designed and prepared. Exploration of the piperidine core examined both the basicity and the location of a nitrogen, as well as conformational variants. The bicyclo-piperidine 24c was found to be the most potent inhibitor of CCR3 with an IC50 of 0.0082 μM in the binding assay and 0.0024 μM in the chemotaxis assay.
- Gong, Leyi,Hogg, J. Heather,Collier, James,Wilhelm, Robert S.,Soderberg, Carol
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p. 3597 - 3600
(2007/10/03)
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- Transition metal complexes in organic synthesis. Part 68: Iron-mediated total synthesis of mukonine and mukonidine by oxidative cyclization with air as the oxidizing agent
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The oxidative cyclization of 5-(2-amino-5-methoxycarbonylphenyl)-substituted tricarbonyl[η4-cyclohexa-1,3-diene]iron complexes by air in protic medium provides the corresponding tricarbonyl[η4-4a,9a-dihydro-9H-carbazole]iron complexes. This procedure is applied to the total synthesis of the 3-methoxycarbonylcarbazole alkaloids mukonine and mukonidine.
- Kn?lker, Hans-Joachim,Wolpert, Marcus
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p. 5317 - 5322
(2007/10/03)
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- Halogenated antituberculosis agents
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Halogenated derivatives of two synthetic anti-tuberculosis agents, thioacetazone and p-aminosalicylic acid, have been synthesized. In general, the halogenated compound has the structure of Structure I: wherein X1is a halogen and X2is a second halogen or hydrogen, and Y is sulfur or oxygen; or, has the structure of Structure IV: wherein X1is a halogen and X2is a second halogen or hydrogen. Alternatively, the halogenated compounds may be pharmaceutically acceptable salts of these compounds. These halogenated derivatives possess anti-mycobacterial activity and are particularly useful for the treatment of Mycobacterium tuberculosis infections. In particular, fluorinated analogs of thioacetazone and p-amino-salicylic acid have been synthesized for use as anti-tuberculosis therapeutic agents either alone or in combination with other conventional anti-tuberculosis therapeutic agents.
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- Synthesis and radiolabeling of (S)-4-amino-5-iodo-2-methoxy-N (1- azabicyclo[2.2.2]oct-3-yl)benzamide, the Active enantiomer of [125i]iodozacopride, and re-evaluation of its 5-HT3 receptor affinity
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We report an improved synthesis of unlabeled (S)-iodozacopride, the radiolabeling of (S)-[125I]iodozacopride via deschloro-(S)-zacopride, and a re-evaluation of its affinity for the 5-HT3 receptor. Unlabeled (S)- iodozacopride was prepared in seven steps from 4-aminosalicylic acid via alkaline hydrolysis of its 4-acetamide derivative. Catalytic hydrogenation of (S)-iodozacopride gave deschloro-(S)-zacopride, identical to that obtained from (S)-3-amino-quinuclidine and 4-amino-2-metihoxybenzoic acid via its corresponding 1-imidazole derivative. Radioiodination to produce (S)- [125I]iodozacopride was accomplished by treatment of deschloro-(S)- zacopride with 5mCi sodium 125iodide and chloramine-T in hydrochloric acid. Purification of the reaction products using an HPLC system capable of detecting chlorinated side-products revealed a mixture of 2.1 mCi (1.3nmol) (S)-[125I]iodozacopride and (S)-zacopride (1.5 nmol). Saturation analysis of the binding of the purified (S)-[125I]iodozacopride to whole rat brain homogenates gave an estimated K(D) of 1.10±0.07 nM. As anticipated, this is approximately haft the K(D) reported for binding of racemic [125I]iodozacopride, and differs from the previously reported value by an order of magnitude. Analysis of the apparent binding affinity of a 1: 1 mixture of (S)-[125I]iodozacopride and (S)-zacopride suggests that the previous result may have been confounded by contamination of the product with unlabeled (S)-zacopride. Competition analysis of the displacement of (S)- [125I]iodozacopride binding by unlabeled (S)-iodozacopride and (S)- zacopride gave K(i) values of 0.95 and 0.21 nM, respectively.
- Hewlett, William A.,De Paulis, Tomas,Mason, N. Scott,Schmidt, Dennis E.,Trivedi, Bakula L.,Zhang, Zhang-Jin,Ebert, Michael H.
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p. 2079 - 2084
(2007/10/03)
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- (S)-4-amino-5-chloro-3-iodo-2-methoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)b enzamide (TRIZAC), a high-affinity ligand for the 5-HT-3 receptor
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TRIZAC is one of the most potent 5-HT-3 receptor antagonist reported to date, having 20-fold higher affinity than (S)-5-iodozacopride. This high affinity (K(i) 0.05 ± 0.01 nM) and a moderate apparent lipophilicity (log P(app) 2.12) makes TRIZAC a promising ligand for studying 5-HT-3 receptors.
- De Paulis, Tomas,Trivedi, Bakula L.,Zhang, Zhang-Jin,Schmidt, Dennis E.,Ebert, Michael H.,Hewlett, William A.
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p. 2657 - 2662
(2007/10/03)
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