- Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction
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A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitor
- Hanusek, Ji?í,Marek, Luká?,Svoboda, Jan,Váňa, Ji?í
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p. 10621 - 10629
(2021/07/31)
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- Synthesis, β-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent
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Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I
- Valverde, Edgar A.,Romero, Angel H.,Acosta, María E.,Gamboa, Neira,Henriques, Genesis,Rodrigues, Juan R.,Ciangherotti, Carlos,López, Simón E.
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supporting information
p. 498 - 506
(2017/11/13)
-
- Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof
-
The invention discloses a beta-carboline derivative targeted to CDK and DNA and a preparation method and medical application thereof. The beta-carboline derivative has a structure shown in the general formula I in the description. The compound can be applied in combination with other antitumor drugs and can also be applied in combination with radiotherapy. The antitumor drugs or radiotherapy and the compound can be applied at the same time or at different times. The combined therapy can perform a synergistic effect, and thus the therapeutic effect can be easily improved.
- -
-
Paragraph 0113
(2017/06/02)
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- Discovery of Selective Inhibitors Targeting Acetylcholinesterase 1 from Disease-Transmitting Mosquitoes
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Vector control of disease-transmitting mosquitoes is increasingly important due to the re-emergence and spread of infections such as malaria and dengue. We have conducted a high throughput screen (HTS) of 17,500 compounds for inhibition of the essential AChE1 enzymes from the mosquitoes Anopheles gambiae and Aedes aegypti. In a differential HTS analysis including the human AChE, several structurally diverse, potent, and selective noncovalent AChE1 inhibitors were discovered. For example, a phenoxyacetamide-based inhibitor was identified with a 100-fold selectivity for the mosquito over the human enzyme. The compound also inhibited a resistance conferring mutant of AChE1. Structure-selectivity relationships could be proposed based on the enzymes' 3D structures; the hits' selectivity profiles appear to be linked to differences in two loops that affect the structure of the entire active site. Noncovalent inhibitors of AChE1, such as the ones presented here, provide valuable starting points toward insecticides and are complementary to existing and new covalent inhibitors.
- Engdahl, Cecilia,Knutsson, Sofie,Ekstr?m, Fredrik,Linusson, Anna
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p. 9409 - 9421
(2016/11/11)
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- Quinoline derivatives and their use
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The invention discloses a quinoline derivative and a usage thereof, a compound with a structure as shown in a formula (I) and or a pharmaceutically acceptable salt of the compound. The compound or the pharmaceutically acceptable salt thereof disclosed by the invention can be applied to the field of preparation of drugs for preventing or treating tumors.
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Paragraph 0099-0101; 0114; 0115; 0117; 0118
(2017/03/14)
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- Hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines catalyzed by palladium-nickel bimetallic nanoparticles
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Since palladium-catalysts have strong abilities for both hydrogenation of nitro-group and hydrogenolysis of benzylamine, they have a much lower chemoselectivity for the hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes. In this article, component stable Pd-Ni bimetallic nanoparticles were prepared by simply heating RANEY-Ni and Na2PdCl4 together in water. They demonstrated novel synergistic effects when they were used as a bimetallic catalyst, by which a highly efficient and chemoselective hydrogenation of (N,N-disubstituted aminomethyl)nitrobenzenes to (N,N-disubstituted aminomethyl)anilines was achieved.
- Bao, Hailin,Wang, Dingsheng,Wang, Xinyan,Cheng, Chuanjie,Li, Yadong,Hu, Yuefei
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p. 47125 - 47130
(2015/06/16)
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- Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPx) mimics and cholinesterase inhibitors against Alzheimer's disease
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A series of ebselen derivatives were designed, synthesised and evaluated as inhibitors of cholinesterases (ChEs) and glutathione peroxidase (GPx) mimics. Most of the compounds were found to be potent against AChEs and BuChE, compounds 5e and 5i, proved to be the most potent against AChE with IC50 values of 0.76 and 0.46 μM, respectively. Among these hybrids, most of the compounds were found to be good GPx mimics compare with ebselen. The selected compounds 5e and 5i were also used to determine the catalytic parameters and in vitro hydrogen peroxide scavenging activity. The results indicate that compounds 5e and 5i may be excellent multifunctional agents for the treatment of AD.
- Luo, Zonghua,Liang, Liang,Sheng, Jianfei,Pang, Yanqing,Li, Jianheng,Huang, Ling,Li, Xingshu
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supporting information
p. 1355 - 1361
(2014/03/21)
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- Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers
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A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized co
- Tang, Li,Zhao, Liying,Hong, Lingjuan,Yang, Fenyan,Sheng, Rong,Chen, Jianzhong,Shi, Ying,Zhou, Naimin,Hu, Yongzhou
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p. 5936 - 5944
(2013/09/23)
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- Discovery and structure-activity relationships of pyrrolone antimalarials
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In the pursuit of new antimalarial leads, a phenotypic screening of various commercially sourced compound libraries was undertaken by the World Health Organisation Programme for Research and Training in Tropical Diseases (WHO-TDR). We report here the detailed characterization of one of the hits from this process, TDR32750 (8a), which showed potent activity against Plasmodium falciparum K1 (EC50 ～ 9 nM), good selectivity (>2000-fold) compared to a mammalian cell line (L6), and significant activity against a rodent model of malaria when administered intraperitoneally. Structure-activity relationship studies have indicated ways in which the molecule could be optimized. This compound represents an exciting start point for a drug discovery program for the development of a novel antimalarial.
- Murugesan, Dinakaran,Mital, Alka,Kaiser, Marcel,Shackleford, David M.,Morizzi, Julia,Katneni, Kasiram,Campbell, Michael,Hudson, Alan,Charman, Susan A.,Yeates, Clive,Gilbert, Ian H.
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supporting information
p. 2975 - 2990
(2013/05/23)
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- Anti-prion activities and drug-like potential of functionalized quinacrine analogs with basic phenyl residues at the 9-amino position
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In this paper, we report the synthesis and cell-based anti-prion activity of quinacrine analogs derived by replacing the basic alkyl side chain of quinacrine with 4-(4-methylpiperazin-I-yl)phenyl, (1-benzylpiperidin-4-yl) and their structural variants. Several promising analogs were found that have a more favorable anti-prion profile than quinacrine in terms of potency and activity across different prion-infected murine cell models. They also exhibited greater binding affinities for a human prion protein fragment (hPrP121-231) than quinacrine, and had permeabilities on the PAMPA-BBB assay that fall within the range of CNS permeant candidates. When evaluated on bidirectional assays on a Pgp overexpressing cell line, one analog was less susceptible to Pgp efflux activity compared to quinacrine. Taken together, the results point to an important role for the substituted 9-amino side chain attached to the acridine, tetrahydroacridine and quinoline scaffolds. The nature of this side chain influenced cell-based potency, PAMPA permeability and binding affinity to hPrP121-231.
- Nguyen, Thuy,Sakasegawa, Yuji,Doh-Ura, Katsumi,Go, Mei-Lin
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experimental part
p. 2917 - 2929
(2011/07/08)
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- Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment
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Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.
- Mayer, Scott C.,Banker, Annette L.,Boschelli, Frank,Di, Li,Johnson, Mark,Kenny, Cynthia Hess,Krishnamurthy, Girija,Kutterer, Kristina,Moy, Franklin,Petusky, Susan,Ravi, Malini,Tkach, Diane,Tsou, Hwei-Ru,Xu, Weixin
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scheme or table
p. 3641 - 3645
(2009/04/06)
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- 4-(Phenylaminomethylene)isoquinoline-1,3(2H,4H)-diones as potent and selective inhibitors of the cyclin-dependent kinase 4 (CDK4)
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The cyclin-dependent kinases (CDKs), as complexes with their respective partners, the cyclins, are critical regulators of cell cycle progression. Because aberrant regulations of CDK4/cyclin D1 lead to uncontrolled cell proliferation, a hallmark of cancer, small-molecule inhibitors of CDK4/cyclin D1 are attractive as prospective antitumor agents. The series of 4-(phenylaminomethylene)isoquinoline-1,3(2H,4H)-dione derivatives reported here represents a novel class of potent inhibitors that selectively inhibit CDK4 over CDK2 and CDK1 activities. In the headpiece of the 4-(phenylaminomethylene) isoquinoline-1,3(2H,4H)-dione, a basic amine substitutent is required on the aniline ring for the CDK4 inhibitory activity. The inhibitory activity is further enhanced when an aryl or heteroaryl substituent is introduced at the C-6 position of the isoquinoline-1,3(2H,4H)-dione core. We present here SAR data and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.
- Tsou, Hwei-Ru,Otteng, Mercy,Tran, Tritin,Floyd Jr., M. Brawner,Reich, Marvin,Birnberg, Gary,Kutterer, Kristina,Ayral-Kaloustian, Semiramis,Ravi, Malini,Nilakantan, Ramaswamy,Grillo, Mary,McGinnis, John P.,Rabindran, Sridhar K.
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experimental part
p. 3507 - 3525
(2009/04/07)
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- 8-HETEROARYLPURINE MNK2 INHIBITORS FOR TREATING METABOLIC DISORDERS
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This invention relates to 8-Heteroarylpurine Mnk2 Inhibitors which are useful for the treatment and prevention of metabolic disorders such as obesity and diabetes.
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Page/Page column 48
(2010/11/28)
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- QUATERNARY SALT CCR2 ANTAGONISTS
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Quaternary salt compounds of Formula (I) or pharmaceutically acceptable forms thereof, which are CCR2 antagonists and are useful in preventing, treating or ameliorating CCR2 mediated inflammatory syndromes, disorders or diseases in a subject in need thereof.
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Page/Page column 54-56
(2008/06/13)
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- Reduction of CYP450 inhibition in the 4-[(1H-imidazol-4-yl)methyl] piperidine series of histamine H3 receptor antagonists
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A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
- Berlin, Michael,Ting, Pauline C.,Vaccaro, Wayne D.,Aslanian, Robert,McCormick, Kevin D.,Lee, Joe F.,Albanese, Margaret M.,Mutahi, Mwangi W.,Piwinski, John J.,Shih, Neng-Yang,Duguma, Luli,Solomon, Daniel M.,Zhou, Wei,Sher, Rosy,Favreau, Leonard,Bryant, Matthew,Korfmacher, Walter A.,Nardo, Cymbelene,West Jr., Robert E.,Anthes, John C.,Williams, Shirley M.,Wu, Ren-Long,Susan She,Rivelli, Maria A.,Corboz, Michel R.,Hey, John A.
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p. 989 - 994
(2007/10/03)
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- THIA-TETRAAZAACENAPHTHYLENE KINASE INHIBITORS
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The present invention is directed to novel thia-tetraazaacenaphthylene compounds of Formula (I): and pharmaceutically acceptable forms thereof and their synthesis and use as inhibitors of ATP-protein kinase interactions.
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Page/Page column 89-90
(2008/06/13)
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- BETA-KETOAMIDE COMPOUNDS HAVING AN MCH-ANTAGONISTIC EFFECT AND MEDICAMENTS CONTAINING SAID COMPOUNDS
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The invention relates to β-ketoamide compounds of general formula (I) wherein the groups and radicals A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b have the designations cited in patent claim 1. The invention also relates to medicaments containing at least one inventive amide. As a result of the MCH receptor antagonistic activity, the inventive medicaments are suitable for treating metabolic disorders and/or eating disorders, especially adipositas, bulimia, anorexia, hyperphagia and diabetes.
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Page/Page column 80
(2008/06/13)
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- Beta-ketoamide compounds with MCH antagonistic activity
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Compounds of formula I wherein the groups and residues A, B, b, X, Y, Z, R1, R2, R3, R5a and R5b have the meanings given in claim 1. The invention further relates to pharmaceutical compositions containing at least one amide according to the invention. As a result of their MCH-receptor antagonistic activity the pharmaceutical compositions according to the invention are suitable for the treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, anorexia, hyperphagia, and diabetes.
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Page/Page column 80
(2008/06/13)
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- Substituted indolines which inhibit receptor tyrosine kinases
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Indolinones of the formula having an inhibitory effect on receptor tyrosine kinases and cyclin/CDK complexes, as well as on the proliferation of endothelial cells and various tumor cells. Exemplary are: (a) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, (b) 3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone, and (c) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-metboxycarbonyl-2-indolinone.
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-
Page column 46
(2008/06/13)
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- Substituted indolinones, their manufacture and their use as medicaments
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The present invention relates to substituted indolinones of general formula wherein R1to R6and X are defined as in claim 1, the isomers and the salts thereof, in particular the physiologically acceptable salts thereof which have valuable pharmacological properties, especially an inhibitory effect on various receptor-tyrosine kinases, and cycline/CDK complexes as well as on the proliferation of endothelial cells and various tumor cells, pharmaceutical compositions containing these compounds, their use and processes for preparing them.
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Page/Page column 24
(2010/02/08)
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- Substituted indolinones, preparation thereof and their use as pharmaceutical compositions
-
Indolinones of general formula I which are inhibitors of cell proliferation, particularly of tumour cells, and inhibitors of protein kinases. The following compounds are exemplary: (Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, (Z)-3-{1 -[4-(N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone, and (Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone.
- -
-
-
- Substituted indolinones with kinase inhibitory activity
-
Substituted indolinones of general formula having effect on various kinases and cycline/CDK complexes and on the proliferation of various tumour cells. Exemplary compounds are: 3-Z-[1-(4-(N-Benzyl-N-methyl-aminomethyl)-phenylamino)-1-methyl-methylene]-5-a
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-
-
- Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety
-
The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium m
- Shiraishi, Mitsuru,Aramaki, Yoshio,Seto, Masaki,Imoto, Hiroshi,Nishikawa, Youichi,Kanzaki, Naoyuki,Okamoto, Mika,Sawada, Hidekazu,Nishimura, Osamu,Baba, Masanori,Fujino, Masahiko
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p. 2049 - 2063
(2007/10/03)
-
- Synthesis of 3--benzazoles as Potential Antibacterial Agents
-
N-(4-Aminobenzyl)-morpholine and piperidine (II) have been prepared and reacted under the conditions of Mannich reaction with benzoxazoles, benzothiazole and benzimidazoline-2-thione to give the title bases (III and IV).A few of these compounds undergo Mc
- Varma, Rajendra S.,Verma, Kaushal K.
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p. 877 - 879
(2007/10/02)
-
