- Design, synthesis, molecular modeling, and antimicrobial potential of novel 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives as DNA gyrase inhibitors
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A series of 3-[(1H-pyrazol-3-yl)imino]indolin-2-one derivatives were designed using the molecular hybridization method, characterized using different spectroscopic techniques, and evaluated for their in vitro antimicrobial activity. Most of the target compounds demonstrated good to moderate antimicrobial activity compared with ciprofloxacin and fluconazole. Four compounds (8b, 9a, 9c, and 10a) showed encouraging results, with minimal inhibitory concentration (MIC) values (53.45–258.32 μM) comparable to those of norfloxacin (100.31–200.63 μM) and ciprofloxacin (48.33–96.68 μM). Noticeably, the four derivatives revealed excellent bactericidal and fungicidal activities, except for the bacteriostatic potential of compounds 8b and 9a against Escherichia coli and Staphylococcus aureus, respectively. The time-killing kinetic study against S. aureus confirmed the efficacy of these derivatives. Furthermore, two of the four promising derivatives, 9a and 10a, could prevent the formation of biofilms of S. aureus without affecting the bacterial growth at low concentrations. A combination study with seven commercial antibiotics against the multidrug-resistant bacterium P. aeruginosa showed a notable reduction in the antibiotic MIC values, represented mainly through a synergistic or additive effect. The enzymatic assay implied that the most active derivatives had inhibition potency against DNA gyrase comparable to that of ciprofloxacin. Molecular docking and density functional theory calculations were performed to explore the binding mode and study the reactivity of the promising compounds.
- Abu-Elghait, Mohammed,Alzahrani, Abdullah Y.,Ammar, Yousry A.,Ragab, Ahmed,Salem, Mohamed A.
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- Design, synthesis, biological evaluation and docking studies of sulfonyl isatin derivatives as monoamine oxidase and caspase-3 inhibitors
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The aim of this study was to design novel multifunctional neuroprotective agents that would slow down or halt neurodegeneration through inhibition of MAO-A, MAO-B and caspase-3. We focused on pharmacophoric groups of known MAO-inhibitors including selegil
- Tavari, Mohsen,Malan, Sarel F.,Joubert, Jacques
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p. 1628 - 1639
(2016/08/24)
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- Phenyl Benzenesulfonylhydrazides Exhibit Selective Indoleamine 2,3-Dioxygenase Inhibition with Potent in Vivo Pharmacodynamic Activity and Antitumor Efficacy
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Tryptophan metabolism has been recognized as an important mechanism in immune tolerance. Indoleamine 2,3-dioxygenase plays a key role in local tryptophan metabolism via the kynurenine pathway and has emerged as a therapeutic target for cancer immunotherapy. Our prior study identified phenyl benzenesulfonyl hydrazide 2 as a potent in vitro (though not in vivo) inhibitor of indoleamine 2,3-dioxygenase. Further lead optimization to improve in vitro potencies and pharmacokinetic profiles resulted in N′-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl hydrazide 40, which demonstrated 59% oral bioavailability and 73% of tumor growth delay without apparent body weight loss in the murine CT26 syngeneic model, after oral administration of 400 mg/kg. Accordingly, 40, is proposed as a potential drug lead worthy of advanced preclinical evaluation.
- Lin, Shu-Yu,Yeh, Teng-Kuang,Kuo, Ching-Chuan,Song, Jen-Shin,Cheng, Ming-Fu,Liao, Fang-Yu,Chao, Min-Wu,Huang, Han-Li,Chen, Yi-Lin,Yang, Chun-Yu,Wu, Mine-Hsine,Hsieh, Chia-Ling,Hsiao, Wenchi,Peng, Yi-Hui,Wu, Jian-Sung,Lin, Li-Mei,Sun, Manwu,Chao, Yu-Sheng,Shih, Chuan,Wu, Su-Ying,Pan, Shiow-Lin,Hung, Ming-Shiu,Ueng, Shau-Hua
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p. 419 - 430
(2016/01/28)
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- Synthesis and antibacterial activity of 1,5-disubstituted indolin-2-one derivatives containing sulfonamides
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A series of novel 1,5-disubstituted indolin-2-one derivatives containing sulfonamides as potential antibacterial agent were synthesized and the antibacterial activity was preliminary evaluated against two Gram-positive bacteria S. aureus ATCC26112, S. aureus SC and Gram-negative bacteria P. vulgaris in vitro. The results indicated that most of the target compounds exhibited promising antibacterial potency. Compounds 7b, 7d and 8b showed notable antimicrobial activity with corresponding inhibition zone (IZ = 19 mm, 21 mm and 23.5 mm, respectively) at the concentration of 100 μg/mL against S. aureus ATCC26112.
- Liang, Qiu-Xian,Liao, Ling,Luo, Juan,Pu, Shuai,Wang, Yu-Liang,Chen, Tian
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p. 2959 - 2963
(2015/12/12)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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Compounds, pyridine N-oxides, and pharmaceutically acceptable salts of formula (I) are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and for preventing and/ or treating diseases of the respiratory tract characterized by airway obstruction, such as asthma or COPD.
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Paragraph 0510
(2013/05/08)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 130
(2013/05/09)
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- ISATIN ANALOGUES AND USES THEREFOR
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Novel isatin analogues, including isatin analogues comprising Michael Acceptors (IMAs) are disclosed. Further disclosed are methods of synthesis of the isatin analogues, and uses of the analogues, including inhibition of caspase-3 and caspase-7, and in vi
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Page/Page column 9
(2009/04/24)
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- 3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3
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Cysteine-dependant aspartyl protease (caspase) activation has been implicated as a part of the signal transduction pathway leading to apoptosis. It has been postulated that caspase-3 inhibition could attenuate cell damage after an ischemic event and thereby providing for a novel neuroprotective treatment for stroke. As part of a program to develop a small molecule inhibitor of caspase-3, a novel series of 3,4-dihydropyrimido(1,2-a)indol-10(2H)-ones (pyrimidoindolones) was identified. The synthesis, biological evaluation and structure-activity relationships of the pyrimidoindolones are described.
- Havran, Lisa M.,Chong, Dan C.,Childers, Wayne E.,Dollings, Paul J.,Dietrich, Arlene,Harrison, Boyd L.,Marathias, Vasilios,Tawa, Gregory,Aulabaugh, Ann,Cowling, Rebecca,Kapoor, Bhupesh,Xu, Weixin,Mosyak, Lidia,Moy, Franklin,Hum, Wah-Tung,Wood, Andrew,Robichaud, Albert J.
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experimental part
p. 7755 - 7768
(2010/03/03)
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- Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds
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Screening of the NCI diversity set of compounds has led to the identification of 5 (NSC-117199), which inhibits the protein tyrosine phosphatase (PTP) Shp2 with an IC50 of 47 μM. A focused library incorporating an isatin scaffold was designed a
- Lawrence, Harshani R.,Pireddu, Roberta,Chen, Liwei,Luo, Yunting,Sung, Shen-Shu,Szymanski, Ann Marie,Yip, M. L. Richard,Guida, Wayne C.,Sebti, Sa?d M.,Wu, Jie,Lawrence, Nicholas J.
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scheme or table
p. 4948 - 4956
(2009/07/11)
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- INHIBITION OF SHP2/PTPN11 PROTEIN TYROSINE PHOSPHATASE BY NSC-87877, NSC-117199 AND THEIR ANALOGS
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Compounds and associated methods for inhibiting a protein tyrosine phosphatase. By a combination of experimental and virtual screenings of the NCI Diversity Set chemical library, NSC-87877 and NSC-117199 have been identified as Shp2 PTP inhibitors. Signif
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Page/Page column 26
(2010/11/28)
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- 5-Pyrrolidinylsulfonyl isatins as a potential tool for the molecular imaging of caspases in apoptosis
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Caspases are the unique enzymes responsible for the execution of the cell death program and may represent an exclusive target for the specific molecular imaging of apoptosis in vivo. 5-Pyrrolidinylsulfonyl isatins represent potent nonpeptidyl caspase inhibitors that may be suitable for the development of caspase binding radioligands (CBRs). (S)-5-[1-(2-Methoxymethylpyrrolidinyl) sulfonyl]isatin (7) served as a lead compound for modification of its N-1-position. Corresponding pairs of N-1-substituted 2-methoxymethyl- and 2-phenoxymethylpyrrolidinyl derivatives were examined in vitro by biochemical caspase inhibition assays. All target compounds possess high in vitro caspase inhibition potencies in the nanomolar to subnanomolar range for caspase-3 (Ki = 0.2-56.1 nM). As shown for compound (S)-1-(4-(2-fluoroethoxy) benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin (35), the class of N-1-substituted 5-pyrrolidinylsulfonyl isatins competitively inhibits caspase-3. All caspase inhibitors show selectivity for the effector caspases-3 and -7 in vitro. The 2-methoxymethylpyrrolidinyl versions of the isatins appear to possess superior caspase inhibition potencies in cellular apoptosis inhibition assays compared with the 2-phenoxymethylpyrrolidinyl inhibitors.
- Kopka, Klaus,Faust, Andreas,Keul, Petra,Wagner, Stefan,Breyholz, Hans-J?rg,H?ltke, Carsten,Schober, Otmar,Sch?fers, Michael,Levkau, Bodo
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p. 6704 - 6715
(2007/10/03)
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- N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: Synthesis, in vitro activity, and molecular modeling studies
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A number of isatin sulfonamide analogues were prepared and their potencies for inhibiting caspase-1, -3, -6, -7, and -8 were evaluated in vitro. Several compounds displaying a nanomolar potency for inhibiting the executioner caspases, caspase-3 and caspas
- Chu, Wenhua,Zhang, Jun,Zeng, Chenbo,Rothfuss, Justin,Tu, Zhude,Chu, Yunxiang,Reichert, David E.,Welch, Michael J.,Mach, Robert H.
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p. 7637 - 7647
(2007/10/03)
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- Pyrimidoindolones and methods for using same
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Novel pyrimidoindolone compounds are disclosed. Methods of using the pyrimidoindolone compounds and compositions containing the compounds in the treatment and/or prevention of disease and other conditions related to inflammation, neurodegeneration, osteoarthritis and apoptosis are also disclosed.
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Page/Page column 21
(2010/02/14)
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- Caspases and apoptosis
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The present invention is to novel compounds of Formula (I), their pharmaceutical compositions, and to the novel inhibition of Caspases for use in the treatment of apoptosis, and disease states caused by excessive or inappropriate cell death.
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- Potent and selective nonpeptide inhibitors of caspases 3 and 7
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5-Dialkylaminosulfonylisatins have been identified as potent, nonpeptide inhibitors of caspases 3 and 7. The most active compound within this series (34) inhibited caspases 3 and 7 in the 2-6 nM range and exhibited approximately 1000-fold selectivity for caspases 3 and 7 versus a panel of five other caspases (1, 2, 4, 6, and 8) and was at least 20-fold more selective versus caspase 9. Sequence alignments of the active site residues of the caspases strongly suggest that the basis of this selectivity is due to binding in the S2 subsite comprised of residues Tyr204, Trp206, and Phe256 which are unique to caspases 3 and 7. These compounds inhibit apoptosis in three cell-based models: human Jurkat T cells, human chondrocytes, and mouse bone marrow neutrophils.
- Lee,Long,Murray,Adams,Nuttall,Nadeau,Kikly,Winkler,Sung,Ryan,Levy,Keller,DeWolf Jr.
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p. 2015 - 2026
(2007/10/03)
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