- Novel benzenesulfonamides aryl and arylsulfone conjugates adopting tail/dual tail approaches: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies
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New series of benzenesulfonamide and benzoic acid derivatives were designed and synthesized using tail/dual tail approach to improve potency and selectivity as carbonic anhydrase inhibitors. The synthesized compounds evaluated as CAIs against isoforms hCA I, II, IV and IX with acetazolamide (AAZ) as standard inhibitor. The benzenesulfonamide derivatives 7a-d, 8a-h, 12a-c, 13a and 15a-c showed moderate to potent inhibitory activity with selectivity toward isoform hCA II, especially, compound 13a with (Ki = 7.6 nM), while the benzoic acid analogues 12d-f, 13b and 15d-f didn't show any activity except compounds 12d,f and 15e that showed weak activity. Additionally, molecular docking was performed for compounds 7a, 8a, 8e, 12a, 13a and 15a on isoform hCA I, II to illustrate the possible interaction with the active site to justify the inhibitory activity.
- Eldeeb, Assem H.,Abo-Ashour, Mahmoud F.,Angeli, Andrea,Bonardi, Alessandro,Lasheen, Deena S.,Elrazaz, Eman Z.,Nocentini, Alessio,Gratteri, Paola,Abdel-Aziz, Hatem A.,Supuran, Claudiu T.
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supporting information
(2021/05/10)
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- Oxadiazole substituted benzenesulfonamide compound and preparation method thereof and application as carbonic anhydrase inhibitor
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The invention discloses an oxadiazole substituted benzenesulfonamide compound as shown in a formula I or pharmaceutically acceptable salt thereof, a preparation method of the oxadiazole substituted benzenesulfonamide compound and an application of the oxadiazole substituted benzenesulfonamide compound as a carbonic anhydrase inhibitor. The compound is simple in preparation process, mild in reaction conditions in key steps, higher in yield, lower in energy consumption and more environment-friendly, and the compound shows a good development potential as a carbonic anhydrase inhibitor.
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Paragraph 0059-0063
(2020/04/02)
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- Palladium-Catalyzed ortho-Benzoylation of Sulfonamides through C?H Activation: Expedient Synthesis of Cyclic N-Sulfonyl Ketimines
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The ortho-carbonylation of sulfonylarenes by non-hazardous aryl aldehydes as a carbonyl precursor was reported. In this method, the sulfonamide group serves as a directing group for C?H activation in the presence of a Pd catalyst under ligand-free conditions. The scope of this strategy has been extended to the one-pot two-step synthesis of cyclic N-sulfonyl ketimines under mild reaction conditions. Our approach could be considered as an alternative by circumventing the use of highly reactive organolithium or Grignard reagents to access a wide range of biologically potent cyclic N-sulfonyl ketimines. (Figure presented.).
- Ojha, Subhadra,Panda, Niranjan
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p. 561 - 571
(2019/12/24)
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- Tail approach synthesis of novel benzenesulfonamides incorporating 1,3,4-oxadiazole hybrids as potent inhibitor of carbonic anhydrase I, II, IX, and XII isoenzymes
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Two new series of 1,3,4-oxadiazole benzenesulfonamide hybrids 3 and 4, having twenty novel compounds, have been designed and synthesized in order to assess their inhibition potential as CAIs against hCA I, II, IX, and XII. ‘Tail approach’ strategy has been used to design the aromatic sulfonamide scaffolds with carbonyl and amide linker. Excellent inhibitory activity against hCA I has been exhibited by compounds 3g and 4j, 3.5 magnitude of order better than reference drug AAZ (KI = 250 nM). Moreover, compound 4j (KI = 7.9 nM) effectively inhibited glaucoma-associated hCA II isoform as well as tumor-associated hCA IX isoform with KI = 16.3 nM. Further hCA XII was weakly inhibited by all the compounds with KI values ranging from 0.23 μM to 3.62 μM. Interestingly structure-activity relationship (SAR) study indicates that N-(3-nitrophenyl)-2-((5-(4-sulfamoylphenyl)-1,3,4-oxadiazol-2-yl)thio)acetamide (4j) is a potent compound to be investigated further for antiglaucoma and antitumor activity. The chemistry of the nature of different substitutions on the 1,3,4-oxadiazole bearing benzenesulfonamide substituted aromatic ring for potency and selectivity over one hCA isoform versus others is deliberated in the present study. In this context, the 1,3,4-oxadiazole motif can be a valuable tool worth developing for the procurement of novel and potent selective CAIs potentially useful for the management of a variety of diseases as chemotherapeutic agents.
- Angeli, Andrea,Kumar, Rajiv,Sharma, Pawan K.,Sharma, Vikas,Supuran, Claudiu T.
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- 4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors
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Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74 μM in an enzymatic assay and 1.37 μM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 μM in the enzymatic assay and 7.54 μM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.
- Yang, Lingling,Chen, Yang,He, Junlin,Njoya, Emmanuel Mfotie,Chen, Jianjun,Liu, Siyan,Xie, Congqiang,Huang, Wenze,Wang, Fei,Wang, Zhouyu,Li, Yuzhi,Qian, Shan
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p. 1087 - 1098
(2019/02/19)
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- Synthesis and comparative carbonic anhydrase inhibition of new Schiff's bases incorporating benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds
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Herein, we report the synthesis, characterization, and carbonic anhydrase (CA) inhibition of the newly synthesized Schiff's bases 4–18 with benzenesulfonamide, methanesulfonamide, and methylsulfonylbenzene scaffolds. The compound inhibition profiles against human CA (hCA) isoforms I, II, IX, and XII were compared to those of the standard inhibitors, acetazolamide (AAZ) and SLC-0111 (a CA inhibitor in Phase II clinical trials for the treatment of hypoxic tumors). The hCA I was inhibited by compounds 4a–8a with inhibition constants (KI) in the range 93.5–428.1 nM (AAZ and SLC-0111: KI, 250.0 and 5080.0 nM, respectively). Compounds 4a–8a proved to be effective hCA II inhibitors, with KI ranging from 18.2 to 133.3 nM (AAZ and SLC-0111: KI, 12.0 and 960.0 nM, respectively). Compounds 4a–8a effectively inhibited hCA IX, with KI in the range 8.5–24.9 nM; these values are superior or equivalent to that of AAZ and SLC-0111 (KI, 25.0 and 45.0 nM, respectively). Compounds 4a–8a displayed effective hCA XII inhibitory activity with KI values ranging from 8.6 to 43.2 nM (AAZ and SLC-0111: KI, 5.7 and 4.5 nM, respectively). However, compounds 9b–13b and 14c–18c were found to be micromolar CA inhibitors. For molecular docking studies, compounds 5a, 6a, and 8a were selected.
- Abdel-Aziz, Alaa A.-M.,Al-Suwaidan, Ibrahim A.,AlSaif, Nawaf A.,Alanazi, Mohammed M.,Bua, Silvia,El-Azab, Adel S.,Hefnawy, Mohamed M.,Nocentini, Alessio,Supuran, Claudiu T.
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- Discovery of potent anti-convulsant carbonic anhydrase inhibitors: Design, synthesis, in vitro and in vivo appraisal
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We report the design, synthesis and pharmacological assessment of novel benzenesulfonamide derivatives acting as effective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the synthesized compounds were screened for their CA inhibitory action against four isoforms of human origin (h), i.e. hCA I, hCA II, hCA VII and hCA IX. In-vitro carbonic anhydrase inhibition studies have shown that first series, 4-(2-(4-(4-substitutedpiperazin-1-yl)benzylidene)hydrazinyl)benzenesulfonamides (4a- 4i) bestowed low nanomolar range to medium nanomolar range inhibitors against hCA II and hCA VII, effectively involved in epileptogenesis. Furthermore, compounds belonging to the second series, 4-(2-(4-(4-substitutedpiperazin-yl)benzylidene)hydrazinecarbonyl)benzenesulfonamides (8a-8k) showed effective inhibition against hCA VII, being less effective against other hCA isoforms. Inspiring with obtained CA inhibition results, we have chosen some of the potent hCA II and hCA VII inhibitors (4g, 4i and 8d) to test their anti-convulsant efficacy in MES and sc-PTZ seizure tests in Swiss Albino male mice. In result, these compounds significantly attenuated both electrical (MES) as well as chemical (sc-PTZ) induced seizures. Next, in advance anticonvulsant tests, compound 8d displayed long duration of action in time course study and successfully attenuated MES induced seizure in mice up to 6 h after drug administration without showing neurotoxicity in rotarod test. Moreover, this compound was also found to be orally active and effectively abolished generalized tonic-clonic seizures in male Wistar rats upon oral administration, being non-toxic in sub acute toxicity studies.
- Mishra, Chandra Bhushan,Kumari, Shikha,Angeli, Andrea,Bua, Silvia,Buonanno, Martina,Monti, Simona Maria,Tiwari, Manisha,Supuran, Claudiu T.
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p. 430 - 443
(2018/07/25)
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- Novel hydrazido benzenesulfonamides-isatin conjugates: Synthesis, carbonic anhydrase inhibitory activity and molecular modeling studies
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As a part of our ongoing efforts towards developing novel carbonic anhydrase inhibitors based on the isatin moiety, herein we report the synthesis and biological evaluation of novel sulfonamides (5a-h, 10a-g and 11a-c) incorporating substituted 2-indolinone moiety (as tail) linked to benzenesulfonamide (as zinc anchoring moiety) through a hydrazide linker. The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, hCA I, II, IX and XII. All these isoforms were inhibited by the sulfonamides reported here in variable degrees. hCA I was inhibited with KIs in the range of 671.8: 3549.5 nM, hCA II in the range of 36.8: 892.4 nM; hCA IX in the range of 8.9: 264.5 nM, whereas hCA XII in the range of 9.0: 78.1 nM. In particular, compound 10b emerged as a single-digit nanomolar hCA IX and XII inhibitor (8.9 and 9.2 nM, respectively). Molecular docking studies carried out for compound 10b within the hCA II, IX and XII active sites allowed us to rationalize the obtained inhibition results.
- Abo-Ashour, Mahmoud F.,Eldehna, Wagdy M.,Nocentini, Alessio,Ibrahim, Hany S.,Bua, Silvia,Abou-Seri, Sahar M.,Supuran, Claudiu T.
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- N-Acylbenzenesulfonamide Dihydro-1,3,4-oxadiazole Hybrids: Seeking Selectivity toward Carbonic Anhydrase Isoforms
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A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racemic mixture led to the isolation of the levorotatory eutomer exhibiting an increase of hCA XII inhibition potency and selectivity with respect to hCA II. Computational studies corroborated these data. Overall our data indicate that both substitution pattern and stereochemistry of dihydro-1,3,4-oxadiazole could be considered as key factors to determine activity and selectivity toward hCA isozymes. These results can provide further indication for the design and optimization of selective hCA inhibitors.
- Bianco, Giulia,Meleddu, Rita,Distinto, Simona,Cottiglia, Filippo,Gaspari, Marco,Melis, Claudia,Corona, Angela,Angius, Rossella,Angeli, Andrea,Taverna, Domenico,Alcaro, Stefano,Leitans, Janis,Kazaks, Andris,Tars, Kaspars,Supuran, Claudiu T.,Maccioni, Elias
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p. 792 - 796
(2017/08/16)
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- SULFONYLAMINOCARBONYL DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USES THEREOF
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This disclosure is related to a sulfonylaminocarbonyl derivative of formula (I) and/or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the sulfonylaminocarbonyl derivatives of formula (I) and/or a pharmaceutically acceptable salt thereof, preparation methods thereof, and use thereof in treating FXR and/or TGR5 mediated diseases, including primary biliary cirrhosis, nonalcoholic fatty liver, portal hypertension, bile acid diarrhea and cholestasis, type II diabetes and obesity, etc.
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Page/Page column 30-31
(2016/11/17)
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- Benzenesulfonamide bearing 1,2,4-triazole scaffolds as potent inhibitors of tumor associated carbonic anhydrase isoforms hCA IX and hCA XII
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Three series of novel heterocyclic compounds (3a-3g, 4a-4g and 5a-5g) containing benzenesulfonamide moiety and incorporating a 1,2,4-triazole ring, have been synthesized and investigated as inhibitors against four isomers of the α-class carbonic anhydrases (CAs, EC 4.2.1.1), comprising hCAs I and II (cytosolic, ubiquitous isozymes) and hCAs IX and XII (transmembrane, tumor associated isozymes). Against the human isozymes hCA I and II, compounds of two series (3a-3g and 4a-4g) showed Ki values in the range of 84-868 nM and 5.6-390 nM, respectively whereas compounds of series 5a-5g were found to be poor inhibitors (Ki values exceeding 10,000 nM in some cases). Against hCA IX and XII, all the tested compounds exhibited excellent to moderate inhibitory potential with Ki values in the range of 2.8-431 nM and 1.3-63 nM, respectively. Compounds 3d, 3f and 4f exhibited excellent inhibitory potential against all of the four isozymes hCA I, II, IX and XII, even better than the standard drug acetazolamide (AZA) whereas compound of the series 5a-5g were comparatively less potent but more selective towards hCA IX and XII.
- Sitaram,Celik, Gulsah,Khloya, Poonam,Vullo, Daniela,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 1873 - 1882
(2014/03/21)
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- In situ formation of vilsmeier reagents mediated by oxalyl chloride: A tool for the selective synthesis of N-sulfonylformamidines
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N-Sulfonylformamidines were produced from sulfonamides or N-acylated sulfonamides using Vilsmeier reagent obtained in situ from N,N-disubstituted formamides and oxalyl chloride. Optically active substrates did not racemize during the process. The efficient and mild cleavage of N-sulfonylformamidines can be achieved with hydrazine hydrate in ethanol. The entire procedure constitutes a simple method for protecting, and deprotecting, the sulfonamide moiety. A straightforward and efficient synthesis for N-sulfonylformamidines by employment of various Vilsmeier reagents generated in situ is described. The reactions proceed under mild reaction conditions and tolerate several sensitive functional groups. Copyright
- Gazvoda, Martin,Kocevar, Marijan,Polanc, Slovenko
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p. 5381 - 5386
(2013/09/02)
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- Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics
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The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.
- Barton, Victoria,Ward, Steven A.,Chadwick, James,Hill, Alasdair,O'Neill, Paul M.
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supporting information; experimental part
p. 4555 - 4559
(2010/08/06)
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- ARYLSULFONYL PYRAZOLINE CARBOXAMIDINE DERIVATIVES AS 5-HT6 ANTAGONISTS
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This invention concerns arylsulfonyl pyrazoline carboxamidine derivatives as antagonists of 5- HT6 receptors, to methods for the preparation of these compounds and to novel intermediates useful for their synthesis. The invention also relates to the uses of such compounds and compositions, particularly their use in administering them to patients to achieve a therapeutic effect in Parkinson's disease, Huntington's chorea, schizophrenia, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease, age related cognitive decline, mild cognitive impairment, sleep disorders, eating disorders, anorexia, bulimia, binge eating disorders, panic attacks, akathisia, attention deficit hyperactivity disorder, attention deficit disorder, withdrawal from abuse of cocaine, ethanol, nicotine or benzodiazepines, pain, disorders associated with spinal trauma or head injury, hydrocephalus, functional bowel disorder, Irritable Bowel Syndrome, obesity and type-2 diabetes. The compounds have the general formula (1) wherein the symbols have the meanings given in the description.
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Page/Page column 26
(2009/10/22)
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- Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus
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Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N′-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF3 substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 μg/mL, and a Clog P value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates.
- Jorge, Salomao Doria,Masunari, Andrea,Rangel-Yagui, Carlota Oliveira,Pasqualoto, Kerly Fernanda Mesquita,Tavares, Leoberto Costa
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experimental part
p. 3028 - 3036
(2009/09/08)
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- PYRAZINE DERIVATIVES AND USE AS PI3K INHIBITORS
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The present invention is related to pyrazine derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infections, kidney diseases, platelet aggregation, cancer, transplantation, graft rejection or lung injuries.
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Page/Page column 49
(2008/06/13)
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- Alpha,beta-unsaturated esters and acids by stereoselective dehydration
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There are provided by the present invention certain pyrazole based CCK-1 receptor modulators which have the general formula: wherein Ar is an aromatic or heteroaromatic group, X is a hydrocarbon linker, Y is a bond or hydrocarbon linker and R1, R2, R3, R4 and R5 are certain organic substituents, methods for making the same, and stereoselective dehydration methods for generally making α,β-unsaturated esters, acids and their derivatives.
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Page/Page column 74-75
(2010/02/15)
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- One-pot and sequential organic chemistry on an enzyme surface to tether a fluorescent probe at the proximity of the active site with restoring enzyme activity
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A new and simple method to tether a functional molecule at the proximity of the active site of an enzyme has been successfully developed without any activity loss. The one-pot sequential reaction was conducted on a surface of human carbonic anhydrase II (hCAII) based on the affinity labeling and the subsequent hydrazone/oxime exchange reaction. The reaction proceeds in a greater than 90% yield in the overall steps under mild conditions. The enzymatic activity assay demonstrated that the release of the affinity ligand from the active site of hCAII concurrently occurred with the replacement by the aminooxy derivatives, so that it restored the enzymatic activity from the completely suppressed state of the labeled hCAII. Such restoring of the activity upon the sequential modification is quite unique compared to conventional affinity labeling methods. The peptide mapping experiment revealed that the labeling reaction was selectively directed to His-3 or His-4, located on a protein surface proximal to the active site. When the fluorescent probe was tethered using the present sequential chemistry, the engineered hCAII can act as a fluorescent biosensor toward the hCAII inhibitors. This clearly indicates the two advantages of this method, that is (i) the modification is directed to the proximity of the active site and (ii) the sequential reaction re-opens the active site cavity of the target enzyme.
- Takaoka, Yousuke,Tsutsumi, Hiroshi,Kasagi, Noriyuki,Nakata, Eiji,Hamachi, Itaru
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p. 3273 - 3280
(2007/10/03)
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- CCK-1 RECEPTOR MODULATORS
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There are provided by the present invention certain pyrazole based CCK-1 receptor modulators which have the general formula: (I) wherein Ar is an aromatic or heteroaromatic group, X is a hydrocarbon linker, Y is a bond or hydrocarbon linker and R1, R2, R3, R4 and R5 are certain organic substituents, and methods of making the same.
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Page/Page column 171-172
(2010/02/10)
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- Carbonic anhydrase inhibitors: Synthesis and inhibition of cytosolic/membrane-associated carbonic anhydrase isozymes I, II, and IX with sulfonamides incorporating hydrazino moieties
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Targeting proteins overexpressed in hypoxic tumors is as an important means of controlling cancer disease. One such protein is the carbonic anhydrase (CA) isoenzyme IX, which in some types of tumors is overexpressed 150-200-fold. We report here a series of sulfonamide derivatives, prepared from 2-carbohydrazido- and 4-carbohydrazido-benzenesulfonamides, which were further derivatized by reaction with aryl isocyanates or arylsulfonyl isocyanates. Several low nanomolar CA IX inhibitors were detected in this way. SAR is discussed for the diverse types of inhibitors and their affinity for different isozymes, with the aim of obtaining isozyme-specific CA IX inhibitors, with putative applications as antitumor drugs.
- Winum, Jean-Yves,Dogné, Jean-Michel,Casini, Angela,De Leval, Xavier,Montero, Jean-Louis,Scozzafava, Andrea,Vullo, Daniela,Innocenti, Alessio,Supuran, Claudiu T.
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p. 2121 - 2125
(2007/10/03)
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- FATTY ACID SYNTHASE INHIBITORS
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This invention relates to the use of compounds as inhibitors of the fatty acid synthase FabH.
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- Acyl sulfonamide anti-proliferatives: Benzene substituent structure-activity relationships for a novel class of antitumor agents
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Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.
- Lobb, Karen L.,Hipskind, Philip A.,Aikins, James A.,Alvarez, Enrique,Cheung, Yiu-Yin,Considine, Eileen L.,De Dios, Alfonso,Durst, Gregory L.,Ferritto, Rafael,Grossman, Cora Sue,Giera, Deborah D.,Hollister, Beth A.,Huang, Zhongping,Iversen, Philip W.,Law, Kevin L.,Li, Tiechao,Lin, Ho-Shen,Lopez, Beatriz,Lopez, Jose E.,Martin Cabrejas, Luisa M.,McCann, Denis J.,Molero, Victoriano,Reilly, John E.,Richett, Michael E.,Shih, Chuan,Teicher, Beverly,Wikel, James H.,White, Wesley T.,Mader, Mary M.
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p. 5367 - 5380
(2007/10/03)
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- CCK-1 RECEPTOR MODULATORS
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There are provided by the present invention certain pyrazole based CCK-1 receptor modulators.
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Page 171-172
(2008/06/13)
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- Substituted pyrrolyl compounds for the treatment of inflammation
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A class of pyrrolyl derivatives is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I STR1 wherein R1, R2, R3 and R4 are as described in the specification.
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- Synthesis and biological activity of nifuroxazide and analogs
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Nifuroxazide and thirteen analogs were synthesized from substituted benzoic acids and minimal inhibitory concentrations were determined using the serial dilution tests, in three sequential steps. Nifuroxazide and chloramphenicol were used as reference standards. The tests were performed in TSB against the standard bacterial strain of Staphylococcus aureus ATCC 25923.
- Tavares,Penna,Amaral
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p. 244 - 249
(2007/10/03)
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- Addition of a Reformatsky Reagent to N-Anthracene-9-sulfonyl and Related Imines: Synthesis of Protected β-Amino Acids
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The Reformatsky reagent tert-butoxycarbonylmethylzinc bromide adds in high yields to N-sulfonylimines, e.g. 1a-1d, derived by condensation of benzaldehyde dimethyl acetal with methanesulfonamide, toluene-4-sulfonamide, 4-(methoxycarbonyl)benzenesulfonamide and sulfamide: the products are protected β-amino acids 2a-2d.N-Deprotection occurs reductively (Na-naphthalene; low yields) for 2b and 2c or hydrolytically (refluxing aq. pyridine; 76percent yield of amino acid 3a after acid hydrolysis of the t-butyl ester) for the sulfamide derivatives 2d.Anthracene-9-sulfonamide (6) is readily available by sulfonation and chlorination of anthracene, and condenses with aldehydes , e.g. in the presence of TiCl4/Et3N, to yield imines 7a-7f, which after addition of tert-butoxycarbonylmethylzinc bromide give protected amino acids 8a-8f; however, 8f cyclizes to the sultam 9 via a spontaneous intramolecular Diels-Alder reaction.Reductive cleavage of the N-anthracene-9-sulfonyl group is much easier than for traditional N-sulfonyl protecting groups, as demonstrated by the deprotection of 8a and 8c using aluminium amalgam.
- Robinson, Andrew J.,Wyatt, Peter B.
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p. 11329 - 11340
(2007/10/02)
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- Treatment of chronic inflammatory joint disease with arylsulfonamides
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A method of treating chronic inflammatory joint disease with arylsulfonamides of the formula: wherein R1 and R2 are selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, loweralkylphenyl, 2 or 3 pyrrolidinyl, 2 or 3-(N-loweralkylpyrrolidinyl, or R1 and R2 taken together may form pyrrolidinyl or piperidinyl heterocyclic amino radicals and Z is an aryl group selected from substituted or unsubstituted tetrazole, 1,3,4-thiadiazole, 1,2,4-triazole, benzothiazole, benzimidazole, imidazole, pyridyl, 4,6-dimethyl pyrimidine, benzene or naphthalene is disclosed.
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- Correlation of Carbon-13 Substituent-Induced Chemical Shifts: meta- and para-Substituted Methyl Benzoates
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Carbon-13 NMR spectra are reported for 69 substituted methyl benzoates in deuteriochloroform or in its mixture with dimethyl sulphoxide-d6.The substituent-induced chemical shifts (SCS) of the CO carbon correlate poorly with dual substituent parameters (DSP) in all possible modifications, and for meta derivatives in particular this correlation is both overparameterized and imprecise.A much better correlation was obtained with parameters (designated Bm, Bp and Cp) derived previously by principal component analysis (PCA) from a larger set.The SCS of the CH3 carbon correlate very well with the original simple Hammett equation, and no DSP treatment is needed.The clustering of substituents is not consequential in such a large set.KEY WORDS Methyl benzoates 13C NMR Substituent effects
- Budesinsky, Milos,Exner, Otto
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p. 585 - 591
(2007/10/02)
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- THERMAL Z,E-ISOMERIZATION OF IMINES. VI. N-ARYLSULFONYLIMINES OF ACETONE AND 2,6-DI-tert-BUTYL-1,4-BENZOQUINONE
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The thermal topomerization of acetone N-arylsulfonylimines and 2,6-di-tert-butyl-1,4-benzoquinone N-arylsulfonyl-4-monoimines was studied by the dynamic PMR method.The inversion mechanism of the topomerization of the N-arylsulfonylimines was established on the basis of an investigation into the electronic and steric effects of substituents at the sulfur atom on the sizes of the barriers to topomerization.The effect of nN-3dS and nN-?c-s* interactions and the induction effect of the arylsulfonyl group on the sizes of the barriers to inversion at the nitrogen atom are considered.The reduction of the barriers to inversion in the N-arylsulfonylimines with increase in the electron-withdrawing characteristics of the para substituents in the aryl ring is largely determined by the increase in the nN-3dS interaction.
- Prosyanik, A.V.,Kol'tsov, N.Yu.,Romanchenko, V.A.,Belov, V.V.,Burmistrov, K.S.,Loban', S.V.
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p. 335 - 342
(2007/10/02)
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