- Synthesis and anticonvulsant properties of 2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives.
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A number of novel 1H-pyrrolo[1,2-a]benzimidazol-1-one derivatives were prepared and their anticonvulsant properties evaluated. The new synthesized compounds proved to possess anticonvulsant effects depending on the nature of substituents at C-6, C-2, and C-3a positions of the polycyclic system. In particular, the 6-chloro-3a-(p-tolyl)-2,3,3a,4-tetrahydro-1H-pyrrolo[1,2-a]benzimidazol-1-one derivative (22) displayed potency fivefold higher than unsubstituted compound (13).
- Chimirri,De Sarro,De Sarro,Gitto,Zappala
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Read Online
- 4 - Fluorine substituted aryl amine compound and synthesis method thereof
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The invention discloses a synthesis method of 4 -fluorine substituted aryl amine compound, which comprises the following steps: 1) taking acyl-protected phenylhydroxylamine as a substrate, and generating 4 -fluorine substituted aniline compound under basic conditions by taking sulfonyl fluoride as a fluorine source in a polar solvent. 2) The deprotection is carried out under dilute acid conditions or Pd by catalytic hydrogenation to give the 4 - fluorine-substituted aryl amine compound. 4 - Fluorine substituted aniline compounds which are synthesized by the invention greatly increase the lipophilic property due to the introduction of fluorine atoms, and can be widely applied to preparation of fluorine-containing drugs and pesticide and dye intermediates. , The adopted raw materials are industrial products, are cheap and easily available, and are commercially available. 4 - Fluoroaryl aniline prepared by the method is high in yield, and the product with the purity 90% can be obtained in a yield of more than ≥ 99%. The method is simple to operate and low in cost, is very suitable for industrialization, and can be widely popularized and used.
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Paragraph 0066-0068
(2021/09/22)
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- Regioselective Radical Arene Amination for the Concise Synthesis ofortho-Phenylenediamines
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The formation of arene C-N bonds directly from C-H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactiveN-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the areneorthoposition. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly toortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuableortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.
- Gillespie, James E.,Morrill, Charlotte,Phipps, Robert J.
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supporting information
p. 9355 - 9360
(2021/07/19)
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- 2-aminobenzimidazoles for leishmaniasis: From initial hit discovery to in vivo profiling
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Leishmaniasis is a major infectious disease with hundreds of thousands of new cases and over 20,000 deaths each year. The current drugs to treat this life-threatening infection have several drawbacks such as toxicity and long treatment regimens. A library of 1.8 million compounds, from which the hits reported here are publicly available, was screened against Leishmania infantum as part of an optimization program; a compound was found with a 2-aminobenzimidazole functionality presenting moderate potency, low metabolic stability and high lipophilicity. Several rounds of synthesis were performed to incorporate chemical groups capable of reducing lipophilicity and clearance, leading to the identification of compounds that are active against different parasite strains and have improved in vitro proper-ties. As a result of this optimization program, a group of compounds was further tested in anticipation of in vivo evaluation. In vivo tests were carried out with compounds 29 (L. infantum IC50: 4.1 μM) and 39 (L. infantum IC50: 0.5 μM) in an acute L. infantum VL mouse model, which showed problems of poor exposure and lack of efficacy, despite the good in vitro potency.
- Ferreira, Rafael Augusto Alves,Junior, Celso de Oliveira Rezende,Martinez, Pablo David Grigol,Koovits, Paul John,Soares, Bruna Miranda,Ferreira, Leonardo L. G.,Michelan-Duarte, Simone,Chelucci, Rafael Consolin,Andricopulo, Adriano D.,Galuppo, Mariana K.,Uliana, Silvia R. B.,Matheeussen, An,Caljon, Guy,Maes, Louis,Campbell, Simon,Kratz, Jadel M.,Mowbray, Charles E.,Dias, Luiz Carlos
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- From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently validated therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C). Through phenotypic screening, we previously discovered a class of small-molecules with a 2,3′-diindolymethane (DIM) skeleton that can decrease the expression of PCSK9. But these compounds have low potency and low metabolically stability. After performing structure-activity relationship (SAR) optimization by nitrogen scan, deuterium substitution and fluorine scan, we identified a series of much more potent and metabolically stable PCSK9 modulators. A preliminary in vivo pharmacokinetic study was performed for representative analogues difluorodiindolyketone (DFDIK) 12 and difluorobenzoimidazolylindolylketone (DFBIIK-1) 13. The in vitro metabolic stability correlate well with the in vivo data. The most potent compound 21 has the EC50 of 0.15 nM. Our SAR studies also indicated that the NH on the indole ring of 21 can tolerate more function groups, which may facilitate the mechanism of action studies and also allow further improvement of the pharmacological properties.
- Xie, Haibo,Yang, Ka,Winston-McPherson, Gabrielle N.,Stapleton, Donnie S.,Keller, Mark P.,Attie, Alan D.,Smith, Kerry A.,Tang, Weiping
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- A Common, Facile and Eco-Friendly Method for the Reduction of Nitroarenes, Selective Reduction of Poly-Nitroarenes and Deoxygenation of N-Oxide Containing Heteroarenes Using Elemental Sulfur
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A transition metal-free, environment-friendly and practical protocol was developed either for the reduction of nitroarenes or for the deoxygenation of N-oxide containing heteroarenes. The reaction proceeded with the use of a non-toxic and cheap feedstock as elemental sulfur in aqueous methanol under relatively mild conditions. Green chemistry credentials were widely favorable compared to traditional and industrial protocols with good E-factors and a low production of waste. The strategy allowed the efficient reduction of a large variety of substituted-nitroarenes including various o-nitroanilines as well as selective reduction of various poly-nitroarenes in excellent yields with a broad substrate scope. The protocol was successfully extended to the deoxygenation of some N-oxide containing heteroarenes, like benzofuroxans, phenazine N,N'-dioxides, pyridine N-oxides, 2H-indazole N1-oxides, quinoxaline N1,N4-dioxides and benzo[d]imidazole N1,N3-dioxides. A gram-scale example for the synthesis of luminol, in green conditions, was reported. A solid mechanism of reaction was proposed from experimental evidences.
- Cerecetto, Hugo,Romero, Angel H.
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supporting information
(2020/03/23)
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- Metal-free Reduction of Nitro Aromatics to Amines with B 2 (OH) 4 /H 2 O
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A metal-free reduction of nitro aromatics mediated by diboronic acid with water as both the hydrogen donor and solvent under mild conditions has been developed. A series of aromatic amines were obtained with good functional group tolerance and in good yields.
- Chen, Danyi,Zhou, Yanmei,Zhou, Haifeng,Liu, Sensheng,Liu, Qixing,Zhang, Kaili,Uozumi, Yasuhiro
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supporting information
p. 1765 - 1768
(2018/06/26)
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- Water as a hydrogen source in palladium-catalyzed reduction and reductive amination of nitroarenes mediated by diboronic acid
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An unprecedented palladium-catalyzed chemoselective reduction and reductive amination of nitroarenes with water as a hydrogen source mediated by diboronic acid have been discovered. A series of aryl amines containing various reducible functional groups were obtained in good to excellent yields.
- Zhou, Yanmei,Zhou, Haifeng,Liu, Sensheng,Pi, Danwei,Shen, Guanshuo
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p. 3898 - 3904
(2017/06/13)
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- Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization
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PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.
- Mao, Ruifeng,Shao, Jingwei,Zhu, Kongkai,Zhang, Yuanyuan,Ding, Hong,Zhang, Chenhua,Shi, Zhe,Jiang, Hualiang,Sun, Dequn,Duan, Wenhu,Luo, Cheng
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p. 6289 - 6304
(2017/08/02)
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- FUSED RING DERIVATIVE AND ORGANIC SOLAR CELL COMPRISING THE SAME
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The present invention relates to a condensed cyclic derivative represented by chemical formula 1, and an organic solar cell containing the same. According to an embodiment of the present invention, the condensed cyclic derivative exhibits excellent coating properties by having a hydroxyl group, an alkyl group, an alkoxy group, and a sulfide group as a substituent.COPYRIGHT KIPO 2017
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Paragraph 0192; 0193; 0194; 0195
(2017/08/02)
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- Graphene oxide (GO) or reduced graphene oxide (rGO): Efficient catalysts for one-pot metal-free synthesis of quinoxalines from 2-nitroaniline
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A straightforward one-pot preparation of library of quinoxalines from 2-nitroanilines under entirely metal-free conditions is described. Initial reduction of nitroaniline with hydrazine hydrate is efficiently catalyzed by graphene oxide (GO) or reduced graphene oxide (rGO), and further one-pot tandem reactions with 1,2-dicarbonyl compounds or with α-hydroxy ketones afford quinoxalines in excellent yields. The catalyst is recovered, characterized, and found to be recyclable for consecutive four runs examined with appreciable conversions.
- Roy, Babli,Ghosh, Sujit,Ghosh, Pranab,Basu, Basudeb
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supporting information
p. 6762 - 6767
(2016/01/30)
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- Synthesis and biological evaluation of 5-substituted derivatives of benzimidazole
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A series of eight novel 5-substituted derivatives of benzimidazole was synthesized by condensation of the corresponding diamine with ethyl 4-[4- -(2-chlorophenyl)piperazin-1-yl]butanoate in refluxing 4 M hydrochloric acid. In vitro antibacterial activity against ten strains, namely Bacillus subtilis, Clostridium sporogenes, Streptosporangium longisporum, Micrococcus flavus, Sarcina lutea, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella enteritidis and Proteus vulgaris and antifungal activity against two fungal strains, namely Candida albicans and Saccharomyces cerevisiae, were evaluated. Of all the compounds screened for activity, 2-{3-[4-(2-chlorophenyl) piperazin-1-yl]propyl}-5-iodo-1H-benzimidazole and 2-{3-[4-(2-chlorophenyl) piperazin-1-yl]propyl}-5-methyl-1H-benzimidazole were associated with higher antifungal activity than commercial drugs.
- Vasic, Vesna P.,Penjisevic, Jelena Z.,Novakovic, Irena T.,Sukalovic, Vladimir V.,Andric, Deana B.,Kostic-Rajacic, Sladana V.
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p. 277 - 282
(2014/04/17)
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- QUINOXALINONES AND DIHYDROQUINOXALINONES AS RESPIRATORY SYNCYTIAL VIRUS ANTIVIRAL AGENTS
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Quinoxalinones and dihydroquinoxalinones having inhibitory activity on RSV replication and having the formula (I) including addition salts, and stereochemically isomeric forms thereof; compositions containing these compounds as active ingredient and processes for preparing these compounds and compositions.
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Page/Page column 24
(2014/08/07)
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- Synthesis of riboflavines, quinoxalinones and benzodiazepines through chemoselective flow based hydrogenations
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Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively.
- Baumann, Marcus,Baxendale, Ian R.,Hornung, Christian H.,Ley, Steven V.,Rojo, Maria Victoria,Roper, Kimberley A.
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p. 9736 - 9759
(2014/08/05)
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- Identification of novel HDAC inhibitors through cell based screening and their evaluation as potential anticancer agents
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A series of benzimidazole based HDAC inhibitors have been rationally designed, synthesized and screened. The SAR of this new chemotype is described. The lead compound, 11e, showed strong activity in several cellular assays and demonstrated in vivo efficacy in mouse xenograft pancreatic cancer models.
- Wang, Tong,Sepulveda, Mario,Gonzales, Paul,Gately, Stephen
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p. 4790 - 4793
(2013/09/02)
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- Synthesis of novel histamine H4 receptor antagonists
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This letter describes the discovery and synthesis of a series of octahydropyrrolo[3,4-c]pyrrole based selective histamine hH4 receptor antagonists. The amidine compound 20 was found to be a potent and selective histamine H4 receptor antagonist with moderate clearance and a high volume of distribution.
- Lane, Charlotte A.L.,Hay, Duncan,Mowbray, Charles E.,Paradowski, Michael,Selby, Matthew D.,Swain, Nigel A.,Williams, David H.
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scheme or table
p. 1156 - 1159
(2012/03/11)
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- Facile synthesis of fluorine-substituted benzothiadiazole-based organic semiconductors and their use in solution-processed small-molecule organic solar cells
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A facile new protocol for the synthesis of iodinated derivatives of fluorinated benzothiadiazoles is demonstrated for the production of p-type semiconducting materials. The newly synthesized small-molecule compounds bis[TPA-diTh]-MonoF-BT and bis[TPA-diTh]-DiF-BT exhibited a power conversion efficiency of 2.95 % and a high open-circuit voltage of 0.85 V in solution-processed small-molecule organic solar cells. A facile new protocol was developed for synthesis of iodinated derivatives of fluorinated benzothiadiazoles as precursors for fluorine-substituted benzothiadiazole-based organic semiconductors 2 and 3, which exhibit enhanced intramolecular charge transfer compared to unfluorinated analogue 1 and hence improved photovoltaic performance in small-molecule organic solar cells (see figure). Copyright
- Cho, Nara,Ko, Jaejung,Song, Kihyung,Lee, Jae Kwan
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supporting information
p. 11433 - 11439,7
(2012/12/12)
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- Facile synthesis of fluorine-substituted benzothiadiazole-based organic semiconductors and their use in solution-processed small-molecule organic solar cells
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A facile new protocol for the synthesis of iodinated derivatives of fluorinated benzothiadiazoles is demonstrated for the production of p-type semiconducting materials. The newly synthesized small-molecule compounds bis[TPA-diTh]-MonoF-BT and bis[TPA-diTh]-DiF-BT exhibited a power conversion efficiency of 2.95 % and a high open-circuit voltage of 0.85 V in solution-processed small-molecule organic solar cells. A facile new protocol was developed for synthesis of iodinated derivatives of fluorinated benzothiadiazoles as precursors for fluorine-substituted benzothiadiazole-based organic semiconductors 2 and 3, which exhibit enhanced intramolecular charge transfer compared to unfluorinated analogue 1 and hence improved photovoltaic performance in small-molecule organic solar cells (see figure). Copyright
- Cho, Nara,Song, Kihyung,Lee, Jae Kwan,Ko, Jaejung
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supporting information
p. 11433 - 11439
(2013/01/14)
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- 1,2,4-OXADIAZOLE SUBSTITUTED PIPERIDINE AND PIPERAZINE DERIVATIVES AS SMO ANTAGONISTS
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The present invention relates to compounds of formula (I): and pharmaceutically acceptable salts, stereoisomers or tautomers thereof which are inhibitors of the Sonic Hedgehog pathway, in particular Smo antagonists. Thus the compounds of this invention are useful for the treatment of diseases associated with abnormal hedgehog pathway activation, including cancer, for example basal cell carcinoma, medulloblastoma, prostate, pancreatic, breast, colon, bone and small cell lung cancers, and cancers of the upper GI tract.
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Page/Page column 67
(2010/04/03)
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- SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
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The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I); or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N- C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
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Page/Page column 102
(2008/12/06)
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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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- Preparation of 6-substituted quinoxaline JSP-1 inhibitors by microwave accelerated nucleophilic substitution
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A small library of 6-aminoquinoxalines has been prepared by nucleophilic substitution of 6-fluoroquinoxaline with amines and nitrogen-containing heterocycles under computer-controlled microwave irradiation. Some compounds were found to be potent inhibitors of JNK Stimulatory Phosphatase-1 (JSP-1) in an in vitro biological assay.
- Zhang, Li,Qiu, Beiying,Li, Xin,Wang, Xin,Li, Jingya,Zhang, Yongliang,Liu, Jian,Li, Jia,Shen, Jingkang
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p. 988 - 999
(2007/10/03)
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- Hyperbranched polyphenylquinoxalines from self-polymerizable AB 2 and A2B monomers
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A self-polymerizable AB2 monomer, 2,3-bis(4-hydroxyphenyl)-6-fluoroquinoxaline, and an A2B monomer, 2,3-bis(4-fluorophenyl)-6-(4-hydrcixyphenoxy)quinoxaline) were prepared and polymerized to afford phenol-terminated and aryl fluoride terminated, hyperbranched polyphenylquinoxalines (HPPQs), respectively. MALDI-TOF analysis showed that intramolecular cyclization was a dominant process for the low molecular weight portion during the polymerizations. After isolation and complete dryness, the phenol-terminated HPPQ 1 was only soluble in strong organic acids, while the aryl fluoride terminated HPPQ 2 was soluble in most common organic solvents. HPPQ 1 was treated with allyl bromide to afford an allyl ether terminated HPPQ 3, which was also soluble in most organic solvents. Intrinsic viscosity measurements and SEC analysis indicated that HPPQ 2 had a much higher Mw and a much broader molecular weight distribution (PDI ~ 60) than HPPQ 1 and HPPQ 3 (PDI ~ 4). The results also suggested that HPPQ 1 formed aggregates in solution and that HPPQ 2 had a much more extended and open conformation. All the HPPQs, which were highly fluorescent, had UV absorption maxima near 375 nm in THF. However, the wavelength of their emission maxima, which ranged from 424 to 466 nm, depended on their end groups.
- Back, Jong-Beom,Harris, Frank W.
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p. 297 - 306
(2007/10/03)
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- 2,4-Bis (trifluoroethoxy)pyridine compound and drug containing the compound
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The present invention is directed to a 2,4-bis(trifluoroethoxy)pyridine compound represented by formula (1): (wherein X1 represents a fluorine atom or a hydrogen atom) or a salt thereof, and to a drug containing the compound or the salt as an active ingredient. The compound has metabolic resistance in human liver microsome, good absorbability upon oral administration, and excellent ACAT inhibitory activity.
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- 6-subtituted-7-heteroquinoxalinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both
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The invention provides compounds with antagonism against excitatory amino acid receptors, in particular, AMPA receptor having 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives and addition salts thereof as effective ingredients, and processes for the preparation of both. The compounds are 6-substituted-7-heteroquinoxalinecarboxylic acid derivatives represented by the formula (1) where A denotes a single bond or methylene (CH2), Y denotes a nitrogen atom or ═CH—, V denotes a single bond or methylene (CH2), T denotes a hydroxyl group, amino group, lower alkoxycarbonyl group, carboxyl group, aldehyde group or the like, Q denotes a halogen atom, lower alkyl group or lower alkoxy group, and R1denotes a hydroxyl group, lower alkoxy group or the like, and addition salts thereof.
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Page/Page column 37
(2010/01/31)
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- Quantitative structure-activity relationships on 5-substituted terbenzimidazoles as topoisomerase I poisons and antitumor agents
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Several 5-substituted terbenzimidazoles were synthesized and evaluated as mammalian topoisomerase I poisons and for cytotoxicity against a human lymphoblastoma cell line, RPMI-8402. No correlation was observed between topoisomerase I poisoning activity and the Hansch π value or the σ(meta) and σ(para) values associated with each substituent. These data suggest that electronic effects and relative lipophilicity of substituents at the 5-position of these terbenzimidazoles do not have a significant effect upon intrinsic topoisomerase I poisoning activity. There was, however, a good correlation between the relative π values for the various subtituents evaluated and cytotoxic activity. Experimentally determined log P values did not correlate well with either cytotoxicity or π values. Capacity factors (log k') as determined by high pressure liquid chromatography did correlate well with the π values of varied substituents and cytotoxicity. These data indicate that the relative lipophilic activity of substituents at the 5-position of these terbenzimidazoles can strongly influence relative cytotoxic activity.
- Kim, Jung Sun,Sun, Qun,Yu, Chiang,Liu, Angela,Liu, Leroy F.,Lavoie, Edmond J.
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p. 163 - 172
(2007/10/03)
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- Synthesis of substituted 2-ethoxycarbonyl- and 2-carboxyquinoxalin -3 ones for evaluation of antimicrobial and anticancer activity
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A series of variously substituted quinoxalin-3-ones bearing an ethoxycarbonyl or carboxy group in the C-2 position has been prepared and their structures proved by 1H NMR spectroscopy. The obtained compounds were investigated in vitro for antimicrobial and anticancer activities. Preliminary results showed a moderate activity against a few strains of bacteria but no significant anticancer and anti-HIV activity.
- Sanna, Paolo,Carta, Antonio,Loriga, Mario,Zanetti, Stefania,Sechi, Leonardo
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p. 455 - 461
(2007/10/03)
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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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- Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors
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Helicobacter pylori urease belongs to a family of highly conserved urea- hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K+- ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pK(a)-value of the pyridine, the pK(a)-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of β- mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 μmol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
- Kuhler,Fryklund,Bergman,Weilitz,Lee,Larsson
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p. 4906 - 4916
(2007/10/03)
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- Polyaza Heterocycles. Part 2. Nucleophilic Substitution of Halogens in Halogenoquinoxalinocinnolines
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10-Chloroquinoxalinocinnoline readily undergoes methoxydechlorination when treated with sodium methoxide.The 1-, 2-, 3-, 4- and 9-chloro isomers are unreactive towards this reagent, but the 9,10-dichloro derivative undergoes substitution of both chlorines (the 10-position being much the more reactive).The 9- and 10-bromo analogues are both unreactive towards sodium methoxide, but the 9- and 10-fluoro analogues are both highly reactive, to the extent that it has not been possible even to isolate the 10-fluoro compound.Routes to 9- and 10-piperidinoquinoxalinocinnolines are described.
- Ahmad, Arshad,Dunbar, Linda J.,Green, Iain G.,Harvey, Ian W.,Shepherd, Thomas,et al.
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p. 2751 - 2758
(2007/10/02)
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- HETEROCYCLIC SYSTEMS CONTAINING BRIDGEHEAD NITROGEN ATOMS. PART LXVIII. REACTION OF 5-FLUOROBENZIMIDAZOLYL-2-THIONE WITH CHLOROACETIC ACID: STUDIES OF ORIENTATION OF CYCLIZATION IN THE SYNTHESES OF 6-FLUORO- AND 7-FLUOROTHIAZOLOBENZIMIDAZOL-3(2H)-ONES
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4-Fluoroaniline on successive acetylation, nitration and hydrolysis affords 4-fluoro-2-nitroaniline which on reduction with Raney nickel and hydrazine hydrate followed by treatment of the resulting diamine with carbon disulphide in situ gives 5-fluorobenzimidazolyl-2-thione.The thione on condensation with chloroacetic acid yields acetic acid which on cyclization in a mixture of acetic anhydride and pyridine furnishes two isomers viz. 6-fluoro- and 7-fluorothiazolobenzimidazol-3(2H)-ones.The condensation of thione with 1,2-dibromoethane affords sym-bis-(5-fluorobenzimidazo-2-yl-mercapto)ethane.The structural assignments for the 6-fluoro- and 7-fluorothiazolobenzimidazol-3(2H)-ones have been made by 1H-NMR spectral data using two different methods.
- Pujari, H. K.,Sharma, B. R.,Dahiya, Rajender,Kumar, Sudhir,Murakami, Yasuoki,Tani, Masanobu
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p. 343 - 355
(2007/10/02)
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- THE FOUR 6-HALO-7-NITROQUINOXALINES
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The study of relative nucleofugicities of nitro and halogen in quinoxalines required the synthesis of the four 6-halo-7-nitroquinoxalines 2a-d.The fluoro-, chloro- and bromo-derivatives were made from the commercially available or readily accessible 1,2-diamino-4-halobenzenes, using the nitration of the corresponding p-toluenesulfonamides.This scheme failed in the case of the iodo compound because of extensive nitro-deiodination.The synthesis of 6-iodo-7-nitroquinoxaline was finally achieved from m-fluoroiodobenzene by taking advantage of the high reactivity of fluorine, compared to iodine, in 2,4-dinitrohalobenzenes.
- Nasielski-Hinkens, Raymonde,Leveque, Pierre,Castelet, Daniel,Nasielski, Jacques
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p. 2433 - 2442
(2007/10/02)
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- ACTIVITE ESTEROLYTIQUE DE COMPOSES ASSOCIANT UNE FONCTION THIOL ET UNE BASE HETEROCYCLIQUE. EXEMPLES DE PROCESSUS BIFONCTIONNEL
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The synthesis of 19 compounds associating a thiol function and a basic heterocycle (i.e. benzimidazole, pyridine, thiazole) is described.Their esterolytic activity towards para nitrophenyl acetate (PNPA) is compared with that of simple monofunctional thiols.The influence of the substituents and of the nature of the basic heterocycle shows that the apparition of a cooperative effect depends both on the relative pKa values (thiol and heterocyclic) and on the possibility of proton exchange via the heterocyclic moiety.Examples of bifonctional process are reported in the case of benzimidazolylmethanethiol compounds, due to a basic assistancce on the neutral form of the thiol function.
- Brembilla, Alain,Roizard, Denis,Lochon, Pierre
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p. 577 - 588
(2007/10/02)
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- An improved synthesis of 3,8-dimethyl-3H-imidazo[4,5-f]quinoxalin-2-amine ("MeIQx") and its 2-14C-labelled analogue.
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The highly mutagenic title compound (MeIQx) was prepared in 21% overall yield from 4-fluoro-o-phenylenediamine. The 3,7-dimethyl isomer may be obtained as a minor by-product. The 14C-label was introduced in the last step through cyclization with [14C]cyanogen bromide. An alternative synthesis of MeIQx from p-fluoroaniline avoided the separation of isomers but gave poorer yield.
- Grivas,Olsson
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- Alkyl 4-(o-aminophenyl)-3-thioallophanates
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Various alkyl 4-(o-aminophenyl)-3-thioallophanates and alkyl 4-(o-alkylaminophenyl)-3-thioallophanates are useful as fungicides and mite ovicides. The compounds are prepared by reacting an o-phenylenediamine with the appropriate alkoxycarbonylisothiocyanate and an exemplary species is methyl 4-(o-aminophenyl)-3-thioallophanate.
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