- Targeting the subpocket in xanthine oxidase: Design, synthesis, and biological evaluation of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives
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Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 μM to 0.629 μM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 μM, which was comparable to febuxostat (IC50 = 0.0236 μM). The structure-activity relationship results revealed that the hydrophobic group at the 4′-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.
- Zhang, Bing,Dai,Bao, Ziyang,Mao, Qing,Duan,Yang,Wang, Shaojie
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Read Online
- Amidino substituted 2-aminophenols: biologically important building blocks for the amidino-functionalization of 2-substituted benzoxazoles
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Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2-aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with the obtained kinetic and thermodynamic parameters indicating full agreement with the experimental observations. The obtained amidines were subjected to a condensation reaction with aryl carboxylic acids that allowed the synthesis of a new library of 5- and 6-amidino substituted 2-arylbenzoxazoles. Their antiproliferative features against four human tumour cell lines (SW620, HepG2, CFPAC-1, HeLa) revealed sub-micromolar activities on SW620 for several cyclic amidino 2-naphthyl benzoxazoles, thus demonstrating the usefulness of the proposed synthetic strategy and promoting amidino substituted 2-aminophenols as important building blocks towards biologically active systems.
- Pti?ek, Lucija,Hok, Lucija,Grb?i?, Petra,Topi?, Filip,Cetina, Mario,Rissanen, Kari,Paveli?, Sandra Kraljevi?,Vianello, Robert,Racané, Livio
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supporting information
p. 2784 - 2793
(2021/04/07)
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- Phenazine and phenothiazine covalent triazine framework material as well as preparation method and application thereof
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The invention discloses a phenazine or phenothiazine covalent triazine framework material and a preparation method and application thereof. After the reaction is finished, water and acid are used for washing, and the obtained solid product is a phenazine
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Paragraph 0124; 0127-0130; 0147-0150; 0157-0160
(2021/10/20)
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- Tetrazole xanthine oxidase inhibitor compound as well as preparation method and application thereof
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The invention belongs to the technical field of medicines and relates to a tetrazole xanthine oxidase inhibitor compound as well as a preparation method and application thereof. The invention providesa tetrazole xanthine oxidase inhibitor compound shown as a general formula I or a pharmaceutically acceptable salt, an isomer, a polymorphic substance and a medicinal solvate and further provides anintermediate for preparing the tetrazole xanthine oxidase inhibitor compound or the pharmaceutically acceptable salt, and a structure of the intermediate is shown as a general formula II, III or IV, wherein R is described as claims and a description.
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Page/Page column 19
(2019/09/14)
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- Compounds with xanthine oxidase inhibition activity, and preparation method and application thereof
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The invention belongs to the technical field of medicines, and relates to compounds with xanthine oxidase inhibition activity, and a preparation method and an application thereof. The invention provides the compounds with xanthine oxidase inhibition activity, represented by general formula I, or pharmaceutically acceptable salts, isomers, polymorphs and medical solvates thereof, and further provides an intermediate for preparing the compounds with xanthine oxidase inhibition activity, or the pharmaceutically acceptable salts thereof. The structure of the intermediate is represented by generalformula II or III shown in the description; and R in the general formulas is as defined in claims and the description.
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Paragraph 0074-0075
(2019/09/16)
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- ANTIBIOTIC COMPOUNDS
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The present invention relates to antibiotic compounds of formula (I), to compositions containing these compounds and to methods of treating bacterial diseases and infections using the compounds. The compounds find application in the treatment of infection with, and diseases caused by, Gram-positive and/or Gram-negative bacteria, and in particular in the treatment of infection with, and diseases caused by, Neisseria gonorrhoeae.
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Page/Page column 77
(2018/03/25)
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- Preparation method of benzo[d]oxazole derivative
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The invention discloses a preparation method of a benzo[d]oxazole derivative, namely 2-chlorobenzo[d]oxazole-5-formamide. With 2-nitro-4-cyanophenol being an initial raw material, the target product is obtained through reducing, ring closure, chlorinating
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Paragraph 0021; 0022
(2017/05/18)
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- Synthesis and antiprotozoal activity of cationic 1,4-diphenyl-1H-1,2,3- triazoles
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Novel dicationic triazoles 1-60 were synthesized by the Pinner method from the corresponding dinitriles, prepared via the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The type and the placement of cationic moieties as well as the nature of arom
- Bakunov, Stanislav A.,Bakunova, Svetlana M.,Wenzler, Tanja,Ghebru, Maedot,Werbovetz, Karl A.,Brun, Reto,Tidwell, Richard R.
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experimental part
p. 254 - 272
(2010/05/02)
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- COMPOUNDS WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds of formula (I) or a salt thereof are provided: wherein R4, R6, R7, R8, Q, A, Y, n are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treat
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Page/Page column 51
(2010/04/27)
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- 2-Arylbenzoxazoles as CETP inhibitors: Substitution and modification of the α-alkoxyamide moiety
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The development of a series of 2-arylbenzoxazole α-alkoxyamide and β-alkoxyamine inhibitors of cholesteryl ester transfer protein (CETP) is described. Highly fluorinated α-alkoxyamides proved to be potent inhibitors of CETP in vitro, and the highly fluorinated 2-arylbenzoxazole β-alkoxyamine 4 showed a desirable combination of in vitro potency (IC50 = 151 nM) and oral bioavailability in the mouse.
- Hunt, Julianne A.,Gonzalez, Silvia,Kallashi, Florida,Hammond, Milton L.,Pivnichny, James V.,Tong, Xinchun,Xu, Suoyu S.,Anderson, Matt S.,Chen, Ying,Eveland, Suzanne S.,Guo, Qiu,Hyland, Sheryl A.,Milot, Denise P.,Sparrow, Carl P.,Wright, Samuel D.,Sinclair, Peter J.
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scheme or table
p. 1019 - 1022
(2010/06/14)
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- COMPOUNDS WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds of formula (I) or a salt thereof are provided: wherein R4, R5, R6, Q, A, Y and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders, cognitive impairments and Alzheimer's Disease are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.
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Page/Page column 73
(2009/04/25)
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- HETERO COMPOUND
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[Problems] To provide a useful compound as an active ingredient for a preventing and/or treating agent for rejection in the transplantation of an organ, bone marrow, or a tissue, an autoimmune disease, or the like, which has an excellent S1P1 a
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Page/Page column 31
(2009/01/24)
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- BENZOTHIAZOLES HAVING HISTAMINE H3 RECEPTOR ACTIVITY
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Certain novel benzothiazoles and benzoxazoles, e.g., 2-(piperazin-1-yl)benzothiazoles and 2-(piperazin-1-yl)benzoxazoles, optionally substituted in the 3 and/or 4 positions of the piperazine rings,! of the general formula (l): having histamine H3 antagonistic activity can be used in pharmaceutical compositions.
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Page/Page column 61
(2008/06/13)
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- CETP INHIBITORS
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Compounds of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis. I
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Page/Page column 35; 42; 92
(2008/06/13)
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- Nonpeptide inhibitors of measles virus entry
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Measles virus (MV) is one of the most infectious pathogens known. Despite the existence of a vaccine, over 500 000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably reverse these statistics. Previously, we described a homology model of the MV fusion protein trimer and a putative binding site near the head-neck region. The resulting model permitted the identification of two nonpeptidic entry inhibitors. Here, we present the design, synthesis, and bioevaluation of several series of fusion inhibitors and describe their structure-activity relationships (SAR). Five simply substituted anilides show low-μM blockade of the MV, one of which (AS-48) exhibits IC50 = 0.6-3.0 μM across a panel of wild-type MV strains found in the field. Molecular field topology analysis (MFTA), a 2D QSAR approach based on local molecular properties (atomic charges, hydrogen-bonding capacity and local lipophilicity), applied to the anilide series suggests structural modifications to improve potency.
- Sun, Aiming,Prussia, Andrew,Zhan, Weiqiang,Murray, Ernest E.,Doyle, Joshua,Cheng, Li-Ting,Yoon, Jeong-Joong,Radchenko, Eugene V.,Palyulin, Vladimir A.,Compans, Richard W.,Liotta, Dennis C.,Plemper, Richard K.,Snyder, James P.
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p. 5080 - 5092
(2007/10/03)
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- COMPOUNDS USEFUL AS A3 ADENOSINE RECEPTOR AGONISTS
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Compounds useful as A3 Adenosine Receptor Agonists. Adenosine analogue-type A3 receptor agonists having an N6 substituent of the formula CR20R21CYCLE where CYCLE is a specified heterocycle, e.g. a substituted pyridyl group or a substituted oxazolyl-containing bicyclic ring. 10
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Page/Page column 55
(2010/02/10)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention is directed to pyrazolopyrimidine derivatives of formula (I) wherein the substituents are defined herein, which are useful as kinase inhibitors and as such are useful for affecting angiogenesis and diseases and conditions associated with angiogenesis.
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- NOVEL ALKYNYL DERIVATIVES AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
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The present invention relates to novel compounds of formula (I) wherein W, n, X and W’ are defined in the description; invention compounds are modulators of metabotropic glutamate receptors - subtype 5 (“mGluR5”) which are useful for the treatment of central nervous system disorders as well as other disorders modulated by mGluR5 receptors.
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Page/Page column 134
(2008/06/13)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, Ra, R2, and R3 are defined as described herein.
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Page/Page column 79
(2010/11/30)
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- Synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives potassium channel openers
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As part of a search for new potassium channel openers, the synthesis and vasorelaxant activity of new 1,4-benzoxazine derivatives derived from transformation of the benzopyran skeleton of cromakalim were described. Several new 1,4-benzoxazine derivatives were provided with significant vasorelaxant activity with an overall pharmacological behavior similar to CRK (1f, 1i, 2d, 2e, 2f and 2i).
- Caliendo, Giuseppe,Perissutti, Elisa,Santagada, Vincenzo,Fiorino, Ferdinando,Severino, Beatrice,Di Villa Bianca, Roberta d'Emmanuele,Lippolis, Laura,Pinto, Aldo,Sorrentino, Raffaella
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p. 2663 - 2669
(2007/10/03)
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- Pyrazolopyrimidines as therapeutic agents
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The present invention provides compounds of Formula I, including pharmaceutically acceptable salts and/or prodrugs thereof, where G, R2, and R3 are defined as described herein.
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- Benzimidazolinones, benzoxazolinones, benzopiperazinones, indanones, and derivatives thereof as inhibitors of factor Xa
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The present application describes inhibitors of factor Xa of formula I: or pharmaceutically acceptable salt forms thereof, wherein W, W1, W2, and W3may be N or C and J, Ja, and Jbcombine to form a substituted carbocycle or heterocycle.
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- IL-8 RECEPTOR ANTAGONISTS
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The present invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the chemokine Interleukin-8 (IL-8).
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- Amidino benzimidazole inhibitors of bacterial two-component systems
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Amidino benzimidazoles have been identified as inhibitors of the bacterial KinA/Spo0F two-component system (TCS). Many of these inhibitors exhibit good in vitro antibacterial activity against a variety of susceptible and resistant Gram-positive organisms.
- Weidner-Wells, Michele A.,Ohemeng, Kwasi A.,Nguyen, Van N.,Fraga-Spano, Stephanie,Macielag, Mark J.,Werblood, Harvey M.,Foleno, Barbara D.,Webb, Glenda C.,Barrett, John F.,Hlasta, Dennis J.
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p. 1545 - 1548
(2007/10/03)
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- A new intramolecular migration of the imino group of O-arylketoximes to the aryl group under the Beckmann condition
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ZrCl4-mediated decomposition of O-arylketoximes in benzene leads to regioselective intramolecular migration of the imino group from the oxygen to the ortho position of the aryl group via electron-deficient nitrogen intermediates.
- Kikugawa, Yasuo,Tsuji, Chiho,Miyazawa, Etsuko,Sakamoto, Takeshi
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p. 2337 - 2339
(2007/10/03)
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to the novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease scates mediated by the chemokine, Interleukin-8 (IL-8). In particular, this invention relates to the novel compounds of Formula (Ia) and their use in treating chemokine mediated diseases wherein the chemokine binds to an IL-8 a or b receptor. Compounds of Formula (Ia) are represented by the structure: STR1 wherein interalia, X is oxygen or sulfur;Rb is NR 6 R. sub.7, alkcyl, aryl, arylC 1-4 alkyl, aryl C 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic or heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, camphor, all of which may be optionally substituted; R 1 is independently selected from hydrogen; halogen; nitro; cyano; C 1-10 alkyl; halosubstituted C 1-10 alkyl; C 2-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; (CR. sub.8 R 8)q S(O) t R 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4 alkyl; aryl C 2-10 alkenyl; aryloxy; aryl C 1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10 alkenyl; heteroaryl C 1-4 alkyloxy; heterocyclic; heterocyclic C 1-4 alkyl; heterocyclicC 1-4 alkyloxy; heterocyclic C 2-10 alkenyl; q is 0 or an integer having a value of 1 to 10; n is an integer having a value of 1 to 3;m is an integer having a value of 1 to 3; Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10 alkyl; C 1-10 alkyl; C 2-10 alkenyl C. sub.1-10 alkoxy; halosubstituted C 1-10 alkoxy; azide; (CR 8 R. sub.8)qS(O) t R 4, (CR 8 R 8)qOR 4 ; hydorxy; hydroxy substituted C. sub.1-4 alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylC. sub.1-4 alkyloxy; aryl C 2-10 alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4 alkyloxy; heteroaryl C 2-10 alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10 alkenyl;or a pharmaceutically acceptable salt thereof.
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- Synthesis, biological activity and conformational study of 1,4- benzoxazine derivatives as potassium channel modulators
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With the aim of discovering new molecules with K+-channel activating properties, we have synthesized derivatives of cromakalim (CRK), an important molecule which shows specific affinity towards K+ channels, by replacing the benzopyrane ring of this reference compound with a 1,4-benzoxazine moiety. A different number of substituents showing a good discrimination between hydrophobic and electronic properties have been inserted at the 6-position of the 1,4-benzoxazine ring. We describe here the synthesis and discuss the solid state conformation of these new molecules. When tested on rat aorta ring precontracted with phenylephrine, two compounds (2c and 2d) showed a concentration-dependent relaxation similar to that measured for cromakalim but less potent than this reference drug.
- Caliendo, Giuseppe,Grieco, Paolo,Perissutti, Elisa,Santagada, Vincenzo,Santini, Antonello,Albrizio, Stefania,Fattorusso, Caterina,Pinto, Aldo,Sorrentino, Raffaella
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p. 957 - 967
(2007/10/03)
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- Facile rearrangements of alkynylamino heterocycles with noble metal cations
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A number of 2-(alkynylamino)-substituted heterocycles have been synthesized. These heterocycles rearrange in the presence of silver(I) and gold(I) salts to give novel 2H-pyrimido[2,1-b]benzoxazoles, 2H-pyrimido[2,1-b]benzothiazoles, and a 2H-pyrimido[2,1-b]benzoselenazole. Two of the the 2H-pyrimido[2,1-b]benzoxazoles were isolated in good yield. The kinetics of the silver tetrafluoroborate-catalyzed rearrangements of selected (alkynylamino)benzoxazoles and benzothiazoles have been examined by 1H NMR in CD3CN. Factors affecting the electron densities of the triple bond and of the nitrogen atom in the heterocycle are important in influencing the rate of rearrangement.
- Lok, Roger,Leone, Ronald E.,Williams, Antony J.
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p. 3289 - 3297
(2007/10/03)
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