- Discovery of Biphenyl-Sulfonamides as Novel β- N-Acetyl- d -Hexosaminidase Inhibitors via Structure-Based Virtual Screening
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Novel insecticidal targets are always in demand due to the development of resistance. OfHex1, a β-N-acetyl-d-hexosaminidase identified in Ostrinia furnacalis (Asian corn borer), is involved in insect chitin catabolism and has proven an ideal target for insecticide development. In this study, structure-based virtual screening, structure simplification, and biological evaluation are used to show that compounds with a biphenyl-sulfonamide skeleton have great potential as OfHex1 inhibitors. Specifically, compounds 10k, 10u, and 10v have Ki values of 4.30, 3.72, and 4.56 μM, respectively, and thus, they are more potent than some reported nonglycosyl-based inhibitors such as phlegmacin B1 (Ki = 26 μM), berberine (Ki = 12 μM), 2 (Ki = 11.2 μM), and 3 (Ki = 28.9 μM). Furthermore, inhibitory kinetic assessments reveal that the target compounds are competitive inhibitors with respect substrate, and based on toxicity predictions, most of them have potent drug properties. The obtained results indicate that the biphenyl-sulfonamide skeleton characterized by simple chemical structure, synthetic tractability, potent activity, and low toxicity has potential for further development in pest management targeting OfHex1.
- Chen, Tao,Li, Wen-Qin,Liu, Zheng,Jiang, Wen,Liu, Tian,Yang, Qing,Zhu, Xiao-Lei,Yang, Guang-Fu
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p. 12039 - 12047
(2021/10/20)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with a defect in glyoxylate metabolism, for example a disease or disorder associated with the enzyme glycolate oxidase (GO) or alterations in oxalate metabolism. Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00472; 00473; 001131; 001132
(2021/01/22)
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- GLYCOLATE OXIDASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme glycolate oxidase (GO). Such diseases or disorders include, for example, disorders of glyoxylate metabolism, including primary hyperoxaluria, that are associated with production of excessive amounts of oxalate.
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Paragraph 00514; 00515; 00516; 001173; 001174; 001175
(2019/07/17)
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- Novel 5-methyl-2-phenylphenanthridium derivatives as FtsZ-targeting antibacterial agents from structural simplification of natural product sanguinarine
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A novel series of 5-methyl-2-phenylphenanthridium derivatives were displayed outstanding activity against a panel of antibiotic-sensitive and -resistant bacteria strains compared with their precursor sanguinarine, ciprofloxacin and oxacillin sodium. Compounds 7 l, 7m and 7n were found to display the most effective activity against five sensitive strains (0.06–2 μg/mL) and three resistant strains (0.25–4 μg/mL). The kinetic profiles indicated that compound 7l possessed the strongest bactericidal effect on S. aureus ATCC25923, with the MBC value of 16 μg/mL. The cell morphology and the FtsZ polymerization assays indicated that these compounds inhibited the bacterial proliferation by interfering the function of bacterial FtsZ. The SARs showed that all the 4-methyl-substituted 5-methyl-2-phenylphenanthridium subseries could be further investigated as the FtsZ-targeting antibacterial agents.
- Liu, Jingru,Ma, Ruxin,Bi, Fangchao,Zhang, Fa,Hu, Chaoyu,Venter, Henrietta,Semple, Susan J.,Ma, Shutao
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supporting information
p. 1825 - 1831
(2018/04/16)
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- One-Pot Palladium-Catalyzed Cross-Coupling Treble of Borylation, the Suzuki Reaction and Amination
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A methodology for a sequential palladium-catalyzed cross-coupling procedure consisting of borylation, the Suzuki reaction and amination has been developed for the assembly of molecules with multi-aryl backbones. The linchpin of this development is the meta-terarylphosphine ligand, Cy*Phine, which has been employed as an air- and moisture-stable precatalyst, Pd(Cy*Phine)2Cl2, to improve the efficiency of one-pot borylation–Suzuki reactions. Additionally, the reactivity of the Pd-Cy*Phine system could be tuned to furnish a one-pot, borylation–Suzuki reaction–amination (BSA) cross-coupling treble. The methodology successfully integrated complementary conditions for three distinctly different and modular reactions. Average yields of 74–94% could be achieved for each segment that cumulatively afforded 50–84% yield over the entire three-step sequence in a single pot. (Figure presented.).
- Jong, Howard,Eey, Stanley T.-C.,Lim, Yee Hwee,Pandey, Sangeeta,Iqbal, Nurul Azmah Bte,Yong, Fui Fong,Robins, Edward G.,Johannes, Charles W.
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supporting information
p. 616 - 622
(2017/02/23)
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- A terphenyl structure containing between the diamine compound and its synthetic method and application
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The invention discloses a diamine compound with a meta-terphenyl structure as well as a synthetic method and application thereof. An amino group is introduced by using an aryl halide through Suzuki reaction, and the functional diamine compound with the meta-terphenyl structure is obtained by virtue of bromination, diazotization, Suzuki coupling and reduction. The synthetic method for the diamine compound is simple and relatively high in yield, and the synthesized compound has certain fluorescence property. The diamine compound can be used for synthesizing high-performance and functional polymers such as polyamide, polyimide, polyamideimide and polyesterimide, and is especially suitable for preparing a soluble, colorless and transparent high-performance functional polyimide material with certain fluorescence property.
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Paragraph 0036; 0037
(2017/04/19)
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- 3-Hydroxypyrimidine-2,4-diones as Selective Active Site Inhibitors of HIV Reverse Transcriptase-Associated RNase H: Design, Synthesis, and Biochemical Evaluations
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Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without siginificantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.
- Tang, Jing,Liu, Feng,Nagy, Eva,Miller, Lena,Kirby, Karen A.,Wilson, Daniel J.,Wu, Bulan,Sarafianos, Stefan G.,Parniak, Michael A.,Wang, Zhengqiang
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p. 2648 - 2659
(2016/04/10)
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- Nickel-catalyzed monoarylation of ammonia
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Structurally diverse (hetero)aryl chloride, bromide, and tosylate electrophiles were employed in the Ni-catalyzed monoarylation of ammonia, including chemoselective transformations. The employed JosiPhos/[Ni(cod)2] catalyst system enables the use of commercially available stock solutions of ammonia, or the use of ammonia gas in these reactions, thereby demonstrating the versatility and potential scalability of the reported protocol. Proof-of-principle experiments established that air-stable [(JosiPhos)NiCl2] precatalysts can be employed successfully in such transformations. Lighten Up: The substrate scope of the title reaction includes (hetero)aryl chloride, bromide, and tosylate electrophiles. The versatility and potential scalability of the reported method is demonstrated by the use of either commercially available stock solutions of ammonia or ammonia gas.
- Borzenko, Andrey,Rotta-Loria, Nicolas L.,Macqueen, Preston M.,Lavoie, Christopher M.,McDonald, Robert,Stradiotto, Mark
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supporting information
p. 3773 - 3777
(2015/03/18)
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- Structure-activity relationship study of E6 as a novel necroptosis inducer
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Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations.
- Mou, Jianfeng,Park, Ann,Cai, Yu,Yuan, Junying,Yuan, Chengye
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supporting information
p. 3057 - 3061
(2015/06/22)
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- A novel 4-aminoantipyrine-Pd(II) complex catalyzes Suzuki-Miyaura cross-coupling reactions of aryl halides
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A simple and efficient catalytic system based on a Pd complex of 4-aminoantipyrine, 4-AAP-Pd(II), was found to be highly active for Suzuki-Miyaura cross-coupling of aryl iodides and bromides with phenylboronic acids under mild reaction conditions. Good to excellent product yields from the cross-coupling reaction can be achieved when the reaction is carried out in ethanol, in the open air, using low loading of 4-AAP-Pd(II) as a precatalyst, and in the presence of aqueous K2CO3 as the base. A variety of functional groups are tolerated.
- Contreras-Celedn, Claudia A.,Mendoza-Rayo, Daro,Rincn-Medina, Jos A.,Chacn-Garca, Luis
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supporting information
p. 2821 - 2826
(2015/02/19)
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- Organogold(I) phosphanes in palladium-catalyzed cross-coupling reactions in aqueous media
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Cross-coupling reaction of organogold(I) phosphanes with organic electrophiles in aqueous media has been investigated. Reactions between isolated aryl-, alkenyl-, or alkynylgold(I) phosphanes and aryl halides or triflates, alkenyl halides, and allyl acetates proceed under palladium catalysis conditions at room temperature or 80 °C in water with THF as a co-solvent. The coupling reactions give good yields and are highly versatile and chemoselective, allowing the presence of free amino or hydroxy groups in the electrophile. This methodology was applied to the preparation of substituted phenylalanine esters in a demonstration that gold(I) organometallics are suitable reagents for metal-catalyzed cross-coupling reactions under protic conditions. Organogold(I) phosphanes react with organic electrophiles in aqueous media under palladium catalysis conditions. The reactions take place at room temperature or 80 °C in water with THF as co-solvent. The coupling is versatile and chemoselective and allows the presence of free amino and hydroxy groups in the electrophile. Copyright
- Pena-Lopez, Miguel,Sarandeses, Luis A.,Perez Sestelo, Jose
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p. 2545 - 2554
(2013/06/05)
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- Glucagon Receptor Modulators
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The present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, A1, A2, A3, A4, L, B1, B2, B3 and B4 are as defined herein. The compounds of Formula I have been found to act as glucagon antagonists or inverse agonists. Consequently, the compounds of Formula I and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon.
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Page/Page column 41
(2012/07/13)
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- Crystal structures and triboluminescence based on trifluoromethyl and pentafluorosulfanyl substituted asymmetric N-phenyl imide compounds
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A series of asymmetric N-phenyl imides with trifluoromethyl and pentafluorosulfanyl substituents at the terminal phenyl position have been prepared. They are colorless both in solution and the solid state, and they show blue emission in the solid state. X-ray crystal structure analysis of trifluoromethyl and pentafluorosulfanyl substituted derivatives revealed highly ordered noncentrosymmetric molecular arrangements with large net-dipole moments related to the piezoelectric behavior. XRD measurements of the powders afforded intense sharp reflection peaks, indicating formation of the lamellar ordering. By grinding with a spatula, their solids showed vivid blue triboluminescence.
- Nakayama, Hikaru,Nishida, Jun-Ichi,Takada, Noriyuki,Sato, Hiroyasu,Yamashita, Yoshiro
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experimental part
p. 671 - 676
(2012/06/15)
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- PROCESS FOR PRODUCING BIARYL COMPOUND
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A method for producing a biaryl compound, comprising reacting an aromatic organic compound with at least one compound selected from the group consisting of aromatic organoboron compounds and boroxine compounds, in the presence of a zero-valent nickel catalyst, phosphine ligand and base.
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Page/Page column 24
(2008/06/13)
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- Glucagon Receptor Antagonists, Preparation and Therapeutic Uses
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The present invention discloses novel compounds of Formula I, or pharmaceutically acceptable salts thereof, which have glucagon receptor antagonist or inverse agonist activity, as well as methods for preparing such compounds. In another embodiment, the in
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Page/Page column 12
(2009/01/20)
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- Novel ATP-competitive kinesin spindle protein inhibitors
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Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D 130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors.
- Parrish, Cynthia A.,Adams, Nicholas D.,Auger, Kurt R.,Burgess, Joelle L.,Carson, Jeffrey D.,Chaudhari, Amita M.,Copeland, Robert A.,Diamond, Melody A.,Donatelli, Carla A.,Duffy, Kevin J.,Faucette, Leo F.,Finer, Jeffrey T.,Huffman, William F.,Hugger, Erin D.,Jackson, Jeffrey R.,Knight, Steven D.,Luo, Lusong,Moore, Michael L.,Newlander, Ken A.,Ridgers, Lance H.,Sakowicz, Roman,Shaw, Antony N.,Sung, Chiu-Mei M.,Sutton, David,Wood, Kenneth W.,Zhang, Shu-Yun,Zimmerman, Michael N.,Dhanak, Dashyant
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p. 4939 - 4952
(2008/03/11)
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- Compounds, compositions and methods
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Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.
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Page/Page column 15
(2010/11/27)
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- Compounds, Compositions and Methods
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Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.
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Page/Page column 16
(2010/11/28)
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- Amide bridged piphenyl or biazaphenyl derivatives
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This invention is concerned with compounds of the formula wherein one of R5, R6 and R7 is and R1 to R13, X1, X2, m and n are defined in the description, and all pharmaceutically
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Page/Page column 34
(2008/06/13)
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- NOVEL HETEROCYCLIC AMIDE DERIVATIVES HAVING DIHYDROOROTATE DEHYDROGENASE INHIBITING ACTIVITY
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Novel heterocyclic amide derivatives having pharmacological effects, that is, compounds represented by the general formula (1) or salts thereof: (1) wherein X1-X2 is S-CH2 or the like; R1 is alkyl or the like; p is 0 to 7; R2 is hydrogen, alkyl, or the like; R3 is hydrogen, alkyl, or the like; Y1-Y2 is CH=CH or the like; R4 is halogeno, alkyl, or the like; q is 0 to 4; and R5 is halogeno, hydrogen, alkyl, or the like.
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Page/Page column 51; 53
(2010/10/20)
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- NOVEL BIPHENYL COMPOUNDS AND THEIR USE
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The invention is directed to certain biphenyl compounds. Specifically, the invention is directed to compounds according to Formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and Y are as defined below, and to pharmaceutically-acceptable salts thereo
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Page/Page column 35
(2010/10/20)
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- Transformation of mutagenic aromatic amines into non-mutagenic species by alkyl substituents: Part II: Alkylation far away from the amino function
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Alkyl and trifluoromethyl derivatives of 4-aminobiphenyl (1) (4ABP) and 2-aminofluorene (7) (2AF) were synthesised and assayed for mutagenicity using Salmonella typhimurium tester strains TA98 and TA100 with and without the addition of S9 mix. Modification of 1 was achieved by attachment of alkyl groups (methyl, ethyl, iso-propyl, n-butyl, tert-butyl) and a trifluoromethyl group (CF3) in the 4′-position, the 3′-position (Me, CF3) and the 3′-, 5′-positions (DiMe, DiCF3). Compound 7 was modified by introduction of alkyl groups (methyl, tert-butyl, adamantyl) and a trifluoromethyl group (CF3) in the 7-position. The derivatives of 1 and 7 show for groups with growing steric demand decreased mutagenic activity. The bulkiest groups (CF3, tert-butyl and adamantyl) induce the strongest effects on the mutagenicity. It was even possible to eliminate the mutagenicity of 1 and 7 by introduction of such substituents. In the last part of the work, we compared the experimental mutagenicities with calculated values derived from QSAR correlations. Our findings show that the predictions for aromatic amines with bulky substituents were generally too high. The strongest deviations were observed in the case of the CF3-, tert-butyl- and the adamantyl-group. Only the parent compounds and derivatives with small alkyl groups were predicted well. These investigations show that "large" substituents have an influence on the mutagenicity caused by their steric demand. To predict the correct mutagenicities of such compounds, it is necessary to introduce steric parameters in the respective QSAR equations which will be done in a forthcoming paper.
- Glende, Carsten,Klein, Markus,Schmitt, Heimo,Erdinger, Lothar,Boche, Gernot
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- Carbocation-like reactivity patterns in X′-substituted-4-biphenylylnitrenium ions
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4-Azido-X′-substituted biphenyls (X′ = 4′-MeO, 4′-Me, 4′-F, 3′-Me, 4′-Cl, H, 3′-MeO, 3′-Cl, 4′-CF3) have been prepared and subjected to 248 nm flash photolysis irradiation in 20:80 acetonitrile:water. Transient X′-substituted 4-biphenylylnitrenium ions 10 (Ar-C6H4-N+H) are observed, with lifetimes ranging from 0.6 ms (4′-MeO) to 26 ns (4′-CF3). These cations are quenched by azide ion, with values of kaz ranging from 6 to 10×109 M-1 s-1, with the majority in the range (9-10)×109. This near constant kaz provides further evidence that arylnitrenium ions are quenched by azide ion at the diffusion limit. The solvent reactivities, plotted in a single-parameter Hammett plot against σ+(X), exhibit a poor correlation, with the points for the para π-electron donors deviating from the correlation line based on the other substituents in the direction of requiring a more negative substituent parameter. The data are more satisfactorily fit to the two-parameter Yukawa-Tsuno equation; the parameter r+ obtained in this fit is 2.8. Thus the resonance interaction of the para π-donor X′-substituents with the positive charge of the cation is underestimated by σ+, a situation that has previously been observed with benzylic-type carbenium ions. The conclusion is made that, in their reaction with water, 4-biphenylylnitrenium ions behave like benzyl cations bearing two additional stabilizing vinyl groups, i.e., as if they had the structure Ar-C+(C-to-C)2 double bond. The inherent reactivity and the pattern of the aryl substituent effects are in fact similar to those in the carbocation series Ar-C+(Ph)2.
- Ren,McClelland
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