- 1-Aryl-3-(4-methoxybenzyl)ureas as potentially irreversible glycogen synthase kinase 3 inhibitors: Synthesis and biological evaluation
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Glycogen synthase kinase 3 (GSK-3)has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC50 = 0.086 ± 0.023 μM)and halomethylketone-substituted benzimidazolylurea 9b (IC50 = 0.13 ± 0.060 μM)displayed high GSK-3β inhibitory activity, in comparison to reference inhibitor AR-A014418 (1, IC50 = 0.072 ± 0.043)in our assay. The results suggest further investigation of 2b and 9b as potential covalent inhibitors of GSK-3β, since a targeted interaction might provide improved kinase-selectivity.
- Venter, Jana,Perez, Concepción,van Otterlo, Willem A.L.,Martínez, Ana,Blackie, Margaret A.L.
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p. 1597 - 1600
(2019/05/02)
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- COMPOUNDS AND USES THEREOF
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The present invention features compounds useful in the treatment of neurological disorders. The compounds of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing neurological disorders.
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Page/Page column 244
(2018/05/17)
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- Cyanato - benzimidazole salt and its preparation method
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The present invention discloses a new metal cyano-substituted benzimidazolide salt having formula (I) and its preparation. This new cyano-substituted benzimidazole derivatives exhibited excellent thermal stability. The organic salt of the present inventio
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- Synthesis and potent antiprotozoal activity of mono/di amidino 2-anilinobenzimidazoles versus Plasmodium falciparum and Trypanosoma brucei rhodesiense
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A series of mono and dicationic new 2-anilinobenzimidazole carboxamidines were prepared in a four step process starting from 4-amino-3-nitrobenzonitrile and corresponding o-phenylenediamines. Their antiparasitic activity against Plasmodium falciparum (P.
- Karaaslan, Cigdem,Kaiser, Marcel,Brun, Reto,G?ker, Hakan
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p. 4038 - 4044
(2016/08/23)
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- NOVEL BENZIMIDAZOLE COMPOUND, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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The present invention relates to a novel benzimidazole compound, a pharmaceutical composition for preventing or treating an inflammatory disease comprising said compound, a use of a novel benzimidazole compound for the manufacture of a medicament for prev
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Page/Page column 109-110
(2011/09/15)
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- Synthesis and biological activity of novel inhibitors of topoisomerase I: 2-Aryl-substituted 2-bis-1H-benzimidazoles
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Inhibitors of topoisomerase I constitute a novel family of antitumor agents. The class of benzimidazole derivatives contains compounds possessing affinity to DNA. For example, fluorescent stains Hoechst 33342 and Hoechst 33258 interact with DNA as ligand
- Singh, Manish,Tandon, Vibha
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experimental part
p. 659 - 669
(2011/03/19)
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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 31-32
(2009/01/24)
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- 7-Substituted Purine Derivatives for Immunosuppression
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The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula III:
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Page/Page column 9
(2008/12/05)
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- 7-SUBSTITUTED PURINE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purinone and related derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formula (III).
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Page/Page column 26-27
(2008/12/05)
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- MEDIATORS OF HEDGEHOG SIGNALING PATHWAYS, COMPOSITIONS AND USES RELATED THERETO
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The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function, ptc loss-of-function or smoothened gain-of-function comprising contacting the cell with a hedgehog antagonist of formula (I) in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize smoothened or hedgehog activity.
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Page/Page column 129
(2008/06/13)
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- Synthesis, crystal structure determination and antiproliferative evaluation of novel benzazoyl benzamides
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A series of benzazoyl-benzamides containing different substituents (7-17) were synthesized by condensation of 2-aminobenzazole derivatives (3a-6) with p-substituted benzoyl chlorides. All compounds were characterized by IR, 1H and 13C NMR, MS and elemental analysis. Crystal structure was determined for the compound (9). Some of the new synthesized compounds (7-17) were screened for antitumor activities. Based on presented in vitro screening results we may conclude that compounds (10, 15a, 15b and 16) showed accentuated cell growth inhibitory activity.
- Starcevic, Kristina,Caleta, Irena,Cincic, Dominik,Kaitner, Branko,Kralj, Marijeta,Ester, Katja,Karminski-Zamola, Grace
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p. 2285 - 2299
(2007/10/03)
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- Synthesis and antiprotozoal activity of some 2-(trifluoromethyl)-1H- benzimidazole bioisosteres
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A series of 2-(trifluoromethyl)-1H-benzimidazole derivatives with various 5- and 6-position bioisosteric substituents (-Cl, -F, -CF3, -CN), namely 1-7, were prepared using a short synthetic route. Each analogue was tested in vitro against the protozoa Giardia intestinalis and Trichomonas vaginalis in comparison with albendazole and metronidazole. Several analogues had IC50 values 1 μM against both species, which make them significantly more potent than either standard. Compound 4 [2,5(6)- bis(trifluoromethyl)-1H-benzimidazole], was 14 times more active than albendazole against T.:vaginalis. This compound (4) also showed moderate antimalarial activity against W2 and D6 strains of Plasmodium falciparum (5.98 and 6.12 μM, respectively). Studying further structure activity relationships through the use of bioisosteric substitution in these benzimidazolic derivatives should provide new leads against protozoal and possibly malarial diseases.
- Navarrete-Vazquez, Gabriel,Rojano-Vilchis, Maria De Monserrat,Yepez-Mulia, Lilian,Melendez, Victor,Gerena, Lucia,Hernandez-Campos, Alicia,Castillo, Rafael,Hernandez-Luis, Francisco
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p. 135 - 141
(2007/10/03)
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- Structural factors controlling the self-assembly of columnar liquid crystals
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A series of disc-shaped molecules were prepared by the condensation of 1,2-diamines with 2,3,6,7-tetrakis(hexyloxy)phenanthrene-9,10-dione to investigate the relationship between changes in molecular structure and the self-assembly of columnar liquid crystalline phases. A comparison of compounds with different core sizes indicated that molecules with larger aromatic cores had a greater propensity to form columnar phases, as did compounds substituted with electron-withdrawing groups. In contrast, molecules with electron-donating substituents were nonmesogenic. The clearing temperature of columnar phases increased linearly with the electron-withdrawing ability of the substituents, as quantified by Hammett σ-values. The observed trends can be rationalized in terms of the strength of π-π interactions between aromatic cores in the liquid crystalline phases and suggest that both electrostatic interactions and dispersion forces play important roles in the self-assembly of these materials.
- Foster, E. Johan,Jones, R. Bradley,Lavigueur, Christine,Williams, Vance E.
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p. 8569 - 8574
(2007/10/03)
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- PURINE AND IMIDAZOPYRIDINE DERIVATIVES FOR IMMUNOSUPPRESSION
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The present invention provides novel purine and imidazopyridine derivatives useful for the prevention and treatment of autoimmune diseases, inflammatory disease, mast cell mediated disease and transplant rejection. The compounds are of the general formulas ( I ) and ( II ).
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Page/Page column 28
(2010/11/24)
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- BASIC AMINE COMPOUND AND USE THEREOF
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Novel amine compounds which are represented by the following formula (1) and efficacious against diseases such as a viral infectious disease with HIV, rheumatism, and cancer metastasis; typically, A 1 and A 2 represent a hydrogen atom or a substitutable monocyclic or polycyclic heteroaromatic ring and W represents a substitutable benzene ring or any group represented by the following formula (10) or (11): where X represents O, CH 2 , C(=O), NR 11 , or CHR 35 and D represents a group represented by the following formula (6): where Q represents a single bond, NR 12 , or a group represented by the formula (13): and Y represents a group represented by the following formula (7) : where z represents a substitutable monocyclic or polycyclic aromatic ring; and B represents -NR 25 R 26 ; and R 1 to R 26 in the above formulae represent a hydrogen atom, an alkyl group, an alkenyl group, or an alkynyl group.
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Page/Page column 53-54; 70-71
(2010/11/24)
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- Influence of phenyl ring disubstitution on bisbenzimidazole and terbenzimidazole cytotoxicity: Synthesis and biological evaluation as radioprotectors
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DNA minor groove binders, Hoechst 33258 and Hoechst 33342, have been reported to protect against radiation-induced DNA-strand breakage, but their mutagenicity and cytotoxicity limit their use as protectors of normal tissue during radiotherapy and as biological radioprotectors during accidental radiation exposure. On the basis of these observations, two new nontoxic disubstituted benzimidazoles were synthesized, one having two methoxy groups (5-(4-methylpiperazin-1-yl)-2-[2′-(3,4-dimethoxyphenyl) -5′-benzimidazolyl]benzimidazole, 5) and another having a methoxy and a hydroxyl group (5-(4-methylpiperazin-1-yl)-2-[2′{2″-(4-hydroxy-3-methoxyphenyl) -5″-benzimidazolyl}-5′-benzimidazolyl]benzimidazole, 6) ortho to each other on the phenyl ring. The radiomodifying effects of these nontoxic ligands were investigated with a human glioma cell line exposed to low linear energy transfer radiation by determining cell survival and cell proliferation compared with effects of the parent compound, Hoechst 33342. Cytotoxicity assayed by analyzing clonogenicity, cell growth, and metabolic Viability showed that both 5 and 6 were nontoxic at 100 μM after 72 h of exposure, whereas Hoechst 33342 resulted in lysis of 77% of these cells in 24 h. Macrocolony assay (clonogenicity) showed that 73%, 92%, and 10% of the cells survived when treated with 100 μM 5, 6, and Hoechst 33342, respectively. Both 5 and 6 did not affect the growth of BMG-1 cells. At 10 μM, 5 and 6 showed 82% and 37% protection against radiation-induced cell death (macrocolony assay) while 100% protection was observed against growth inhibition. Disubstitution of the phenyl ring has not only reduced cytotoxicity but also enhanced DNA-ligand stability, conferring high degree of radioprotection.
- Tawar, Urmila,Jain, Akash K.,Dwarakanath,Chandra, Ramesh,Singh, Yogendra,Chaudhury,Khaitan, Divya,Tandon, Vibha
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p. 3785 - 3792
(2007/10/03)
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- Amidine compounds
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A compound of the formula [I] wherein R1, R2and R3are the same or different and each is hydrogen atom, wherein each symbol is as defined in the specification, a salt thereof or a prodrug thereof. The compound of the presen
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- PROLINE DERIVATIVES AND USE THEREOF AS DRUGS
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The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.
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- Synthesis of some new 2-substituted-phenyl-1H-benzimidazole-5-carbonitriles and their potent activity against Candida species
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New 2-substituted-phenyl-1H-benzimidazole-5-carboxylic acids (35, 38), ethyl-5-carboxylate (36), -5-carboxamides (37, 39),-5-carboxaldehyde (42), -5-chloro (40), -5-trifluoromethyl (41), and -5-carbonitriles (44-53, 55-67), -6-carbonitrile (54) were prepa
- G?ker, Hakan,Ku?, Canan,Boykin, David W.,Yildiz, Sulhiye,Altanlar, Nurten
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p. 2589 - 2596
(2007/10/03)
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- Syntheses and emission properties of novel violet-blue emissive aromatic bis(diazaborole)s
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Violet-blue emission from novel aromatic bis(diazaborole)s, which were synthesized by the reaction of 2,5-bis(hexyloxy)-1,4-phenylenediboronic acid and 1,2-phenylenediamine derivatives or diaminonaphthalene derivatives, is described. White-blue emission front a 4-methoxy-1,2-phenylenediamine-derived molecule was observed in DMF using 340 nm as the excitation wavelength.
- Maruyama, Sumio,Kawanishi, Yuji
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p. 2245 - 2249
(2007/10/03)
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- Sulfonamide bridging compounds that inhibit tryptase activity
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The present invention is directed to compounds which are capable of inhibiting the activity of tryptase. Such compounds are useful in the treatment or prevention of inflammatory disease, particularly those disease states which are mediated by mast cell activation. Also encompassed by the invention are formulations comprising the noted compounds, processes for preparing such compounds and methods for treating or preventing an inflammatory disease.
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- Compounds and compositions as anticoagulants
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The present invention relates to novel biheterocyclic derivatives which are factor Xa inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.
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- Structure-based design of potent, amidine-derived inhibitors of factor Xa: Evaluation of selectivity, anticoagulant activity, and antithrombotic activity
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To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule I was docked into the act
- Wiley, Michael R.,Weir, Leonard C.,Briggs, Steven,Bryan, Nancy A.,Buben, John,Campbell, Charles,Chirgadze, Nickolay Y.,Conrad, Richard C.,Craft, Trelia J.,Ficorilli, James V.,Franciskovich, Jeffry B.,Froelich, Larry L.,Gifford-Moore, Donetta S.,Goodson Jr., Theodore,Herron, David K.,Klimkowski, Valentine J.,Kurz, Kenneth D.,Kyle, Jeffery A.,Masters, John J.,Ratz, Andrew M.,Milot, Guy,Shuman, Robert T.,Smith, Tommy,Smith, Gerald F.,Tebbe, Ann Louise,Tinsley, Jennifer M.,Towner, Richard D.,Wilson, Alexander,Yee, Ying K
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p. 883 - 899
(2007/10/03)
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- Heterocyclic topoisomerase poisons
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The invention provides a topoisomerase poison of formula I: wherein R1-R8 have any of the meanings defined in the specification, or a pharmaceutically acceptable salt thereof, as well as pharmaceutical compositions comprising a compound of formula I or a salt thereof, intermediates useful for preparing a compound of formula I, and therapeutic methods comprising administering a compound of formula I or a salt thereof.
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- IL-8 RECEPTOR ANTAGONISTS
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This invention relates to the use of phenyl ureas of formulas (I) and (II) in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8). The variables of (I) and (II) are defined herein. STR1
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- Glycine receptor antagonists and the use thereof
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Methods of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the hyperactivity of the excitatory amino acids, as well as treating anxiety, chronic pain, convulsions, inducing anesthesia and treating psychosis are disclosed by administering to an animal in need of such treatment a compound having high affinity for the glycine binding site, lacking PCP side effects and which crosses the blood brain barrier of the animal. Also disclosed are novel 1,4-dihydroquinoxaline-2,3-diones, and pharmaceutical compositions thereof. Also disclosed are highly soluble ammonium salts of 1,4-dihydroquinoxaline-2,3-diones.
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- Substituted 2,5'-bi-1H-benzimidazoles: Topoisomerase I inhibition and cytotoxicity
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Several 2'-aryl-5-substituted-2,5'-bi-1H-benzimidazole derivatives were synthesized and evaluated as topoisomerase I poisons and for their cytotoxicity toward the human lymphoblast cell line RPMI 8402. This study focused on 18 2,5'-bi-1H-benzimidazole der
- Jung Sun Kim,Gatto,Yu,Liu,Liu,LaVoie
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p. 992 - 998
(2007/10/03)
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- Methods of combating pneumocystis carinii pneumonia and compounds useful therefor
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Disclosed is a method of combating Pneumocystis carinii Pneumonia in a subject in need of such treatment. The method comprises administering to the subject an effective Pneumocystis carinii-combating amount of a bis-benzimidazole compound such as bis[5-(2-imidazolyl)-2-benzimidazolyl]methane, 1,4-bis[5-2-imidazolyl)-2-benzimidazolyl]butane, or a pharmaceutically acceptable salt thereof. Pharmaceutical formulations for carrying out the method and novel compounds are also disclosed, along with methods of combating Giardia lamblia.
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- Synthesis and evaluation of terbenzimidazoles as topoisomerase I inhibitors
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The synthesis and pharmacological activity of a series of terbenzimidazoles are described. The ability of these derivatives to induce DNA cleavage in the presence of topoisomerase I was evaluated in vitro. These analogs were also assayed for their cytotoxicity in RPMI 8402 cells and the camptothecin-resistant CPT-K5 cells. In addition the potential for these compounds to serve as substrates for MDR1 was also determined. Several terbenzimidazoles exhibited similar cytotoxicity against variants of human tumor cells that either overexpress MDR1 or are camptothecin-resistant.
- Sun,Gatto,Yu,Liu,Liu,LaVoie
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p. 3638 - 3644
(2007/10/03)
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- DNA Binding Compounds. VI. Synthesis and Characterization of 2,5'-Disubstituted Bibenzimidazoles Related to the DNA Minor Groove Hoechst 33258
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A series of compounds have been synthesized in which the basic 2-phenylbibenzimidazole structure of Hoechst 33258 has been modified to include various combinations of bromo, iodo, methoxy, amino, alkylamino and nitro groups in the terminal phenyl ring.Both sequential and convergent synthetic routs have been followed using coupling reactions of both imino ethers and aldehydes to 1,2-diamines.All these compounds were characterized by a combination of f.a.b. mass spectrometry and 1H and 13C n.m.r. spectroscopy including inverse detection of long-range heteronuclear CH correlations (HMBC).
- Kelly, David P.,Bateman, Stuart A.,Hook, Robert J.,Martin, Roger F.,Reum, Monica E.,et al.
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p. 1751 - 1770
(2007/10/02)
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- Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles)
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A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA)·poly(dT), poly(dA-dT)·poly-(dA-dT), and poly(dG-dC)·poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (ΔT(m)) and viscosity. The compounds show a greater affinity for poly(dA)·poly(dT) and poly(dA-dT)·poly(dA-dT) than for poly(dG-dC)·poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.
- Fairley,Tidwell,Donkor,Naiman,Ohemeng,Lombardy,Bentley,Cory
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p. 1746 - 1753
(2007/10/02)
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- Process for the manufacture of benzimidazolones-(2)
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Process for the manufacture of benzimidazolones-(2) wherein an o-phenylenediamine is reacted with optionally alkylated urea in the ratio of 1 to 1.3 moles per mole o-phenylenediamine in an organic solvent which has a solubility in water of not more than 5 g/l and has a boiling point above 100° C, at a temperature between 100° and 200° C.
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