- Studies toward the total synthesis of the variolins: Rapid entry to the core structure
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The pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine core structure of the variolins has been synthesized in three steps from commercially available materials. The key reaction involves the deoxygenation and concomitant cyclization of a triarylmethanol using the
- Anderson, Regan J.,Morris, Jonathan C.
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- Structure–Activity Relationships of 2-Sufonylpyrimidines as Quorum-Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa
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Drug-resistant Pseudomonas aeruginosa (PA) strains are on the rise, making treatment with current antibiotics ineffective. Hence, circumventing resistance or restoring the activity of antibiotics by novel approaches is of high demand. Targeting the Pseudomonas quinolone signal quorum sensing (PQS-QS) system is an intriguing strategy to abolish PA pathogenicity without affecting the viability of the pathogen. Herein we report the structure–activity relationships of 2-sulfonylpyrimidines, which were previously identified as dual-target inhibitors of the PQS receptor PqsR and the PQS synthase PqsD. The SAR elucidation was guided by a combined approach using ligand efficiency and ligand lipophilicity efficiency to select the most promising compounds. In addition, the most effective inhibitors were rationally modified by the guidance of QSAR using Hansch analyses. Finally, these inhibitors showed the capacity to decrease biofilm mass and extracellular DNA, which are important determinants for antibiotic resistance.
- Thomann, Andreas,Brengel, Christian,B?rger, Carsten,Kail, Dagmar,Steinbach, Anke,Empting, Martin,Hartmann, Rolf W.
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Read Online
- In vitro identification of imidazo[1,2-a]pyrazine-based antileishmanial agents and evaluation of L. major casein kinase 1 inhibition
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Leishmaniasis constitutes a severe public health problem, with an estimated prevalence of 12 million cases. This potentially fatal disease has a worldwide distribution and in 2012, the fatal Visceral Leishmaniasis (VL) was declared as new emerging disease in Europe, mainly due to global warming, with expected important public health impact. The available treatments are toxic, costly or lead to parasite resistance, thus there is an urgent need for new drugs with new mechanism of action. Previously, we reported the discovery of CTN1122, a potent imidazo[1,2-a]pyrazine-based antileishmanial hit compound targeting L-CK1.2 at low micromolar ranges. Here, we described structurally related, safe and selective compounds endowed with antiparasitic properties, better than miltefosine, the reference therapy by oral route. L-CK1.2 homology model gave the first structural explanations of the role of 4-pyridyl (CTN1122) and 2-aminopyrimidin-4-yl (compound 21) moieties, at the position 3 of the central core, in the low micromolar to nanomolar L-CK1.2 inhibition, whereas N-methylpyrazole derivative 11 remained inactive against the parasite kinase.
- Bazin, Marc-Antoine,Cojean, Sandrine,Pagniez, Fabrice,Bernadat, Guillaume,Cavé, Christian,Ourliac-Garnier, Isabelle,Nourrisson, Marie-Renée,Morgado, Cathy,Picot, Carine,Leclercq, Olivier,Baratte, Blandine,Robert, Thomas,Sp?th, Gérald F.,Rachidi, Najma,Bach, Stéphane,Loiseau, Philippe M.,Le Pape, Patrice,Marchand, Pascal
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- Pyrimidine-containing tri-substituted imidazole compound and application thereof
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The invention relates to a pyrimidine-containing tri-substituted imidazole compound and application thereof. The compound has a structure shown as a formula (I). The compound can be used for effectively inhibiting EGFR (epidermal growth factor receptor) C797S mutation including EGFR ex19del/T790M/C797S and L858R/T790M/C797S; meanwhile, the compounds also have high inhibitory activity on single-point mutation L858R, ex19del and double-point mutation such as L858R/T790M, ex19del/T790M and the like, and moreover, the compounds have a weak inhibitory effect on wild EGFR (epidermal growth factor receptor), namely, the compounds have very good selectivity. The compound has potential to become a drug for treating malignant tumors carrying EGFR C797S mutation, especially non-small cell lung cancer(NSCLC), and has great application value.
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Paragraph 0242; 0248
(2020/07/15)
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- Azine and Diazine Functionalization Using 2,2,6,6-Tetramethylpiperidino-Based Lithium-Metal Combinations: Application to the Synthesis of 5,9-Disubstituted Pyrido[3′,2′:4,5]pyrrolo[1,2- c ]pyrimidines
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The synthesis of triaryl methanols was investigated by reacting different 4-metalated 2-substituted pyrimidines with diaryl ketones, the latter being generated by deprotocupration-aroylation of azine and diazine substrates. Cyclization of the triaryl meth
- Marquise, Nada,Nguyen, Tan Tai,Chevallier, Floris,Picot, Laurent,Thiéry, Valérie,Lozach, Olivier,Bach, Stéphane,Ruchaud, Sandrine,Mongin, Florence
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p. 2811 - 2816
(2015/12/18)
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- Synthesis of mono- and diaza-'pyridones' via stille coupling of alkoxystannanes
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Various alkoxy-substituted heterocyclic stannanes provide access to the corresponding substituted 'pyridone' moieties via Stille cross-coupling. Both pyridyl and a series of diazinyl stannanes are prepared, and options for unmasking (via demethylation or debenzylation) of the pyridone unit are evaluated. Georg Thieme Verlag Stuttgart. New York.
- Smith, Charlotte L.,Hirschh?user, Christoph,Malcolm, Georgia K.,Nasrallah, Daniel J.,Gallagher, Timothy
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p. 1904 - 1908
(2014/08/18)
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- Synthesis and antiproliferative activity of pyridinylcarbonylpyrimidines against melanoma cell line
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The synthesis of the series of pyrimidinylamines 1a-d and pyrimidinylureas 1e-u bearing a novel pyridinylcarbonylpyrimidine scaffold and their antiproliferative activities against A375 human melanoma cell line were described. Among them, three compounds 1
- Ahn, Hyemi,Lee, Jun A.,Kim, Hwan,Oh, Chang-Hyun,Lee, So Ha,Sim, Taebo,Hah, Jung-Mi,Kim, Dong Jin,Yoo, Kyung Ho
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experimental part
p. 1209 - 1214
(2011/11/06)
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- Synthesis of cytimidine through a one-pot copper-mediated amidation cascade
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A concise synthesis of cytimidine was developed utilizing tandem Cu-mediated N-aryl amidations followed by global deprotection. This sequence exploits a regioselective coupling of an iodobenzamide with a halopyrimidine that allows the union of three fragments in a single synthetic manipulation and will permit the efficient and rapid diversification of the cytimidine core.
- Serrano, Catherine M.,Looper, Ryan E.
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supporting information; experimental part
p. 5000 - 5003
(2011/11/13)
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- 2-Pyrimidinyl Pyrazolopyridine ErbB Kinase Inhibitors
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The present invention provides 2-pyrimidinyl pyrazolopyridine compounds, compositions containing the same, as well as processes for the preparation and their use as pharmaceutical agents.
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Page/Page column 34-35
(2009/06/27)
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- MACROLIDES DERIVATIVES AS ANTIBACTERIAL AGENTS
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The present invention provides macrolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram-positive, gram-negative or anaerobic bacteria
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Page/Page column 18
(2009/05/28)
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- 2-Pyrimidinyl Pyrazolopyridine Erbb Kinase Inhibitors
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The present invention provides 2-pyrimidinyl pyrazolopyridine compounds, compositions containing the same, as well as processes for the preparation and their use as pharmaceutical agents.
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Page/Page column 32
(2008/06/13)
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- 4-AZA INDOLE DERIVATIVES AND THEIR USE AS FUNGICIDES
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The present invention relates to a method of preventing and/or controlling fungal infection in plants and/or plant propagation material comprising applying to the plant or plant propagation material a fungicidally effective amount of a compound of formula
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Page/Page column 115
(2008/12/08)
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- MACROLIDES DERIVATIVES AS ANTIBACTERIAL AGENTS
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The present invention provides macrolide derivatives, which can be used as antibacterial agents. Compounds described herein can be used for treating or preventing conditions caused by or contributed to by gram-positive, gram-negative or anaerobic bacteria
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Page/Page column 26; 33
(2010/11/27)
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- NOVEL INHIBITORS OF RHO-KINASES
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Novel inhibitors of Rho-kinases are disclosed.
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Page/Page column 55; 56
(2010/02/15)
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- NEW SUBSTITUTED 1,3-THIAZOLE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVING IMMUNOSUPPRESSION AND INFLAMMATION INHIBITORY ACITIVITY, INTERMEDIATE COMPOUNDS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, A PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
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Disclosed relates to new substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppresion and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same. The compound of the present invention having excellent TNF-α inhibitory activity and inflammation inhibitory activity can be effectively used in the prevention and treatment of TNF-α related diseases.
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Page/Page column 122
(2010/11/25)
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- Pyrazolopyridine antiherpetics: SAR of C2′ and C7 amine substituents
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A novel series of potent pyrazolo[1,5-a]pyridine inhibitors of herpes simplex virus 1 replication have been identified. Several complimentary synthetic methods were developed to allow facile access to a diverse set of analogs from common late stage interm
- Johns, Brian A.,Gudmundsson, Kristjan S.,Turner, Elizabeth M.,Allen, Scott H.,Samano, Vicente A.,Ray, John A.,Freeman, George A.,Boyd Jr., F. Leslie,Sexton, Connie J.,Selleseth, Dean W.,Creech, Katrina L.,Moniri, Kelly R.
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p. 2397 - 2411
(2007/10/03)
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- Concise total syntheses of variolin B and deoxyvariolin B
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The total synthesis of the marine alkaloid variolin B has been achieved in 8 steps and 17% overall yield, starting from commercially available 4-chloro-2-methylthiopyrimidine. The key reaction involves the tandem deoxygenation and cyclization of a triarylmethanol using a combination of triethylsilane and trifluoroacetic acid. In addition, the deoxygenated analogue was prepared in 6 steps and 23% overall yield, starting from the same starting material.
- Anderson, Regan J.,Hill, Jonathan B.,Morris, Jonathan C.
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p. 6204 - 6212
(2007/10/03)
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- PYRADAZINE COMPOUNDS AS GSK-3 INHIBITORS
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The present invention relates generally to inhibitors of the kinases, such as GSK3, and more particularly to fused pyradazine compounds according to formula (I) and methods of their use.
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- N-phenyl-4-pyrazolo[1,5-6]pyridazin-3-ylpyrimidin-2-amines as potent and selective inhibitors of glycogen synthase kinase 3 with good cellular efficacy
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Glycogen synthase kinase 3 regulates glycogen synthase, the rate-determining enzyme for glycogen synthesis. Liver and muscle glycogen synthesis is defective in type 2 diabetics, resulting in elevated plasma glucose levels. Inhibition of GSK-3 could potentially be an effective method to control plasma glucose levels in type 2 diabetics. Structure-activity studies on a N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine series have led to the identification of potent and selective compounds with good cellular efficacy. Molecular modeling studies have given insights into the mode of binding of these inhibitors. Since the initial leads were also potent inhibitors of CDK-2/CDK-4, an extensive SAR was performed at various positions of the pyrazolo[1,5-b] pyridazin core to afford potent GSK-3 inhibitors that were highly selective over CDK-2. In addition, these inhibitors also exhibited very good cell efficacy and functional response. A representative example was shown to have good oral exposure levels, extending their utility in an in vivo setting. These inhibitors provide a viable lead series in the discovery of new therapies for the treatment of type 2 diabetes.
- Tavares, Francis X.,Boucheron, Joyce A.,Dickerson, Scott H.,Griffin, Robert J.,Preugschat, Frank,Thomso, Stephen A.,Wang, Tony Y.,Zhouf, Hui-Qiang
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p. 4716 - 4730
(2007/10/03)
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- BENZAMIDE DERIVATIVES USEFUL AS HISTONE DEACETYLASE INHIBITORS
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The invention concerns a compound of the formula (I) wherein Ring A is heterocyclyl; m is 0-4 and each R1 is a group such as hydroxy, halo, trifluoromethyl and cyano; R2 is halo and n is 0-2; and each R4 is a group such as hydroxy, halo, trifluromethyl and cyano; p is 0-4; and R3 is amino or hydroxy; or pharmaceutically-acceptable salts or in-vivo-hydrolysable ester or amide thereof processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by histone deacetylase
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Page/Page column 63
(2008/06/13)
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- STANNYLATION REACTIONS AND CROSS-COUPLINGS IN PYRIMIDINES
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Pyrimidines have been stannylated in the activated 4-position by thermal decarboxylation of the corresponding carboxylic organotin esters.The decarboxylation can be catalyzed by bis(acetonitrile)palladium(II) dichloride. 4-Iodopyrimidines are 4-stannylate
- Majeed, Amera J.,Antonsen, Oyvind,Benneche, Tore,Undheim, Kjell
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p. 993 - 1006
(2007/10/02)
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