- 2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn)
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Swapping the substituents in positions 2 and 4 of the previously synthesized but yet undisclosed 5-cyano-4-(methylthio)-2-arylpyrimidin-6-ones 4, ring closure, and further optimization led to the identification of the potent antitubercular 2-thio-substituted quinazolinone 26. Structure-activity relationship (SAR) studies indicated a crucial role for both meta-nitro substituents for antitubercular activity, while the introduction of polar substituents on the quinazolinone core allowed reduction of bovine serum albumin (BSA) binding (63c, 63d). While most of the tested quinazolinones exhibited no cytotoxicity against MRC-5, the most potent compound 26 was found to be mutagenic via the Ames test. This analogue exhibited moderate inhibitory potency against Mycobacterium tuberculosis thymidylate kinase, the target of the 3-cyanopyridones that lies at the basis of the current analogues, indicating that the whole-cell antimycobacterial activity of the present S-substituted thioquinazolinones is likely due to modulation of alternative or additional targets. Diminished antimycobacterial activity was observed against mutants affected in cofactor F420 biosynthesis (fbiC), cofactor reduction (fgd), or deazaflavin-dependent nitroreductase activity (rv3547), indicating that reductive activation of the 3,5-dinitrobenzyl analogues is key to antimycobacterial activity.
- Jian, Yanlin,Forbes, He Eun,Hulpia, Fabian,Risseeuw, Martijn D. P.,Caljon, Guy,Munier-Lehmann, Hélène,Boshoff, Helena I. M.,Van Calenbergh, Serge
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p. 440 - 457
(2021/01/14)
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- Discovery of 5-(4-methylpiperazin-1-yl)-2-nitroaniline derivatives as a new class of SIRT6 inhibitors
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SIRT6 is a deacetylase of histone H3 and inhibitors of SIRT6 have been thought as potential agents for treatment of diabetes. Herein we report the discovery of a series of new SIRT6 inhibitors containing the skeleton 1-phenylpiperazine. Among them, compound 5-(4-methylpiperazin-1-yl)-2-nitroaniline (6d) is the most potent one, which showed an IC50 value of 4.93 μM against SIRT6 in the Fluor de Lys (FDL) assay. It displayed KD values of 9.76 μM and 10 μM in surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) assays, respectively. In selectivity assay, 6d showed no activity against other members of the HDAC family (SIRT1-3 and HDAC1-11) at concentrations up to 200 μM. In a mouse model of type 2 diabetes, 6d could significantly increase the level of glucose transporter GLUT-1, thereby reducing blood glucose. Overall, this study provides a promising lead compound for subsequent drug discovery targeting SIRT6.
- Chen, Xiuli,Huang, Shenzhen,Li, Linli,Li, Wenpei,Sun, Weining,Tian, Chenyu,Yang, Shengyong
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supporting information
(2020/06/08)
-
- Synthesis, docking, 3-D-qsar, and biological assays of novel indole derivatives targeting serotonin transporter, dopamine D2 receptor, and mao-a enzyme: In the pursuit for potential multitarget directed ligands
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A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1H-3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7(a-o) and (2-{4-[3-(1H-3-indolyl) -propyl]-1-piperazinyl}-acetylamine)-N-(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13(a-l) were synthesized and evaluated as novel multitarget ligands towards dopamine D2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying Ki values from 5 to 10 nM. Compounds 7k, Ki = 5.63 ± 0.82 nM, and 13c, Ki = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D2 receptor in the nanomolar range (7n: Ki = 307 ± 6 nM and 7m: Ki = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D2 receptor (D2/SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q2 = 0.625, 0.523 for CoMFA and CoMSIA and r2ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).
- Alarcón-Espósito, Jazmín,Araya-Maturana, Ramiro,Cabezas, David,Cerda-Cavieres, Christopher,Chung, Hery,Iturriaga-Vásquez, Patricio,Mella-Raipán, Jaime,Ojeda-Gómez, Claudia,Pessoa-Mahana, Carlos D.,Pessoa-Mahana, Hernán,Quiroz, Gabriel,Reyes-Parada, Miguel,Rodríguez-Lavado, Julio,Saitz, Claudio
-
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- Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors
-
A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC50 = 5 nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.
- Hou, Weijie,Ren, Yan,Zhang, Zhenhua,Sun, Huan,Ma, Yongfen,Yan, Bo
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p. 1740 - 1750
(2018/03/12)
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- Copper-Catalyzed Domino Reaction Involving Nitro as an Unexpected Leaving Group: Construction of Dibenzo-Fused Azepinone Ring
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A copper-catalyzed new domino reaction allowed the facile and direct construction of the dibenzo-fused azepinone ring leading to an array of novel small molecules. The co-catalyst, ligand or additive free one-pot method afforded a unique class of function
- Sunke, Rajnikanth,Ramarao, E. V. Venkat Shivaji,Nallapati, Suresh Babu,Medisetti, Raghavender,Kulkarni, Pushkar,Kapavarapu, Ravi Kumar,Bankala, Ramudu,Parsa, Kishore V. L.,Pal, Manojit
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supporting information
p. 3201 - 3205
(2016/10/21)
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- SUBSTITUTED AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USE
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The invention relates to the preparation and use of new aminopyrimidine derivatives as drug candidates in free form or in pharmaceutically acceptable salt form and formulations thereof for the modulation of a disorder or disease which is mediated by the activity of the PI3K enzymes. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of disorders or diseases, such as disorders of immunity and inflammation in which PI3K enzymes play a role in leukocyte function, and hyperproliferative disorders associated with PI3K activity, including but not restricted to leukemias and solid tumors, in mammals, especially humans.
- -
-
Paragraph 413
(2016/10/04)
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- TETRAHYDROISOQUINOLIN-2-YL-(QUINAZOLIN-4-YL) METHANONE COMPOUNDS AS CANCER CELL GROWTH INHIBITORS
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Tetrahydroisoquinolin-2-yl-(quinazolin-4-yl)methanone derivatives represented by formula (I), pharmacologically acceptable salts thereof, and compositions containing such compounds are described. Methods for treating hyperproliferative disorders by administering the compounds are also described. 1,2,3,4-tetrahydroisoquinoline derivatives for making tetrahydroisoquinolin-2-yl-(quinazolin-4-yl)methanone compounds are also described.
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Page/Page column 39-40
(2014/09/29)
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- Silver-and gold-mediated domino transformation: A strategy for synthesizing benzo[ e ]indolo[1,2-a ]pyrrolo/pyrido[2,1-c ][1,4]diazepine-3,9-diones
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We reported a strategy for the synthesis of fused heterocyclic compounds benzo[e]indolo[1,2-a]pyrrolo/pyrido[2,1-c][1,4]diazepine-3,9-diones via an AgSbF6/gold-complex catalyzed one-pot cascade transformation. The strategy is tolerant of a broad range of substrates and affords a series of intriguing fused diazepinedione heterocycles.(Figure Presented)
- Zhou, Yu,Li, Jian,Ji, Xun,Zhou, Wei,Zhang, Xu,Qian, Wangke,Jiang, Hualiang,Liu, Hong
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experimental part
p. 1239 - 1249
(2011/04/26)
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- CONDENSED AZINE - DERIVATIVES FOR THE TREATMENT OF DISEASES RELATED TO THE ACETYLCHOLINE RECEPTOR
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The present invention relates to a heterocyclic derivative of formula (I) wherein the variables are as defined in the specification or to a pharmaceutically acceptable salt or solvate thereof. The present invention further relates to pharmaceutical compositions comprising said heterocyclic derivatives and to their use in therapy, for instance in the treatment or prevention of disorders mediated by nicotinic acetylcholine receptors, such as schizophrenia and Alzheimer's disease.
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Page/Page column 29
(2011/05/05)
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- The synthesized novel fluorinated compound (LJJ-10) induces death receptor- and mitochondria-dependent apoptotic cell death in the human osteogenic sarcoma U-2 OS cells
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We designed the 6-fluoro-2-(3-fluorophenyl)-4-substituted anilinoquinazoline derivatives as less toxic anti-cancer candidates. Our result demonstrated that LJJ-10 has greater cytotoxicity than that of the other compounds in human osteogenic sarcoma U-2 OS cells. LJJ-10-induced apoptosis was associated with enhancing ROS generation, DNA damage, and an increase of the protein levels of Fas, FasL, FADD, caspase-8, cytochrome c, Apaf-1, AIF, Endo G, caspase-9 and caspase-3 in U-2 OS cells. LJJ-10-triggered growth inhibition was significantly attenuated by N-acetylcysteine, cyclosporine A, anti-FasL monoclonal antibody, and caspase-8, -9 and -3 specific inhibitors in U-2 OS cells. We suggest that LJJ-10-induced apoptotic cell death in U-2 OS cells through death receptor- and mitochondria-dependent apoptotic signaling pathways.
- Hour, Mann-Jen,Yang, Jai-Sing,Chen, Tai-Lin,Chen, Kuan-Tin,Kuo, Sheng-Chu,Chung, Jing-Gung,Lu, Chi-Cheng,Chen, Chia-Yi,Chuang, Yi-Hsuan
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experimental part
p. 2709 - 2721
(2011/06/27)
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- HOMOGENEOUS TIME RESOLVED FLUORESCENCE BASED TEST SYSTEM
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The present invention concerns a fluorescence resonance energy transfer based high throughput test system to measure the formation of the HIV gp41 six-helix bundle. In a first embodiment the current invention relates to a homogeneous time resolved fluorescence-based test system comprising a first helical polypeptide consisting essentially of the sequence of IQN36 (SEQ ID NO:1); a second helical polypeptide consisting essentially of the sequence of C34 (SEQ ID NO: 2) wherein said IQN36 is labeled with a light emitting fluorophore and said C34 is labeled with an ultra-violet excitable fluorophore.
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Page/Page column 46-47
(2010/12/29)
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- HETEROCYCLIC COMPOUNDS AND THEIR USES
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Substituted bicyclic heteroaryls and compositions containing them, for the treatment of general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, including but not restricted to autoimmune diseases such as systemic lupus erythematosis (SLE), myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiples sclerosis, Sjoegren's syndrome and autoimmune hemolytic anemia, allergic conditions including all forms of hypersensitivity. The present invention also enables methods for treating cancers that are mediated, dependent on or associated with p110δ activity, including but not restricted to leukemias, such as Acute Myeloid leukaemia (AML) Myelo-dysplastic syndrome (MDS) myelo-proliferative diseases (MPD) Chronic Myeloid Leukemia (CML) T-cell Acute Lymphoblastic leukaemia (T-ALL) B-cell Acute Lymphoblastic leukaemia (B-ALL) Non Hodgkins Lymphoma (NHL) B-cell lymphoma and solid tumors, such as breast cancer.
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Page/Page column 25; 26
(2011/01/05)
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- Identification of novel and potent 2-amino benzamide derivatives as allosteric glucokinase activators
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The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.
- Nishimura, Teruyuki,Iino, Tomoharu,Mitsuya, Morihiro,Bamba, Makoto,Watanabe, Hitomi,Tsukahara, Daisuke,Kamata, Kenji,Sasaki, Kaori,Ohyama, Sumika,Hosaka, Hideka,Futamura, Mayumi,Nagata, Yasufumi,Eiki, Jun-ichi
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scheme or table
p. 1357 - 1360
(2009/10/15)
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- AMIDE DERIVATIVES
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The invention concerns a compound of the Formula (I) wherein m is 1-2 and each R1 is a group such as cyano, halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R2 is trifluoromethyl or (1-6C)alkyl; R3 is hydrogen and R4 is , (1-6C)alkyl or (1-6C)alkoxy; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical conditions mediated by cytokines.
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Page/Page column 53-54
(2010/11/26)
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- 2- (4-0X0-4H-QUINAZ0LIN-3-YL) ACETAMIDES AND THEIR USE AS VASOPRESSIN V3 ANTAGONISTS
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The present invention relates to 2-(4-oxo4H-quinazolin-3-yl)acetamicle derivatives of formula (I), and to their use as vasopressin V3 antagonists, particularly for the treatment of depression.
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Page/Page column 41-42
(2010/11/23)
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- 4-0X0QUINAZ0LIN-3-YL BENZAMIDE DERIVATIVES FOR THE TREATMENT OF CYTOKINE DISEASES
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The invention concerns a compound of the Formula (I) wherein m is 1-2 and each R1 is a group such as cyano, halogeno, trifluoromethyl heterocyclyl and heterocyclyloxy; R2 is trifluoromethyl or (1-6C)alkyl; R3 is hydrogen or halogeno; and R4 is isoxazolyl;or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of diseases or medical condions mediated by cytokines.
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Page/Page column 52-53
(2008/06/13)
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- PYRIMIDINE DERIVATIVES
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Novel pyrimidine derivatives of formula (I) to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.
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Page/Page column 85; 86
(2008/06/13)
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- PHENYL-SUBSTITUTED QUINOLINE AND QUINAZOLINE COMPOUNDS FOR THE TREATMENT OF DIABETES
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The invention relates to 2-phenyl-substituted quinoline and quinazoline compounds, pharmaceutical compositions, and methods for treating diabetes and related disorders.
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Page/Page column 43
(2010/10/20)
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- BENZOTRIAZEPINONE DERIVATIVES
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The present invention is concerned with benzotriazepinone derivatives, their intermediates, uses thereof and processes for their production. In particular, the present invention relates to parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrp) receptor ligands, (PTH-l or PTH/PTHrp receptor ligands). The invention also relates to methods of preparing such ligands and to compounds which are useful as intermediates in such methods.
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Page/Page column 78
(2010/11/25)
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- NOVEL AMINOBENZAMIDE DERIVATIVE
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This invention relates to a novel compound represented by the formula (I): or a pharmaceutically acceptable salt thereof, ???wherein ???R1 is -S(O)p-A, -S-(O)q-B or -O-D, wherein p and q, which are the same or different, each represent an integ
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-
-
- Design and synthesis of pyrrolo[2,1-c][1,4]benzodiazepine (PBD)- polyaminoalkyl conjugates by the use of SNAr reaction of 2-nitro-5-fluorobenzoate precursor as key reaction
-
The design and synthesis of a series of pyrrolo[2,1-c][1,4]benzodiazepine (PBD)- polyaminoalkyl conjugates as DNA minor groove binders are described. To introduce polyaminoalkyl groups to the pyrrolo[2,1-c][1,4]benzodiazepine pharmacophore, SNA
- Iida, Hirokazu,Hayashi, Naoto,Lown, J. William,Matsumoto, Kiyoshi
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p. 693 - 711
(2007/10/03)
-
- Structure-activity relationships of substituted benzothiophene-anthranilamide factor Xa inhibitors
-
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.
- Chou, Yuo-Ling,Davey, David D.,Eagen, Keith A.,Griedel, Brian D.,Karanjawala, Rushad,Phillips, Gary B.,Sacchi, Karna L.,Shaw, Kenneth J.,Wu, Shung C.,Lentz, Dao,Liang, Amy M.,Trinh, Lan,Morrissey, Michael M.,Kochanny, Monica J.
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p. 507 - 511
(2007/10/03)
-
- Synthesis of polyaminoalkyl substituted conjugates of pyrrolo[2,1- c][1,4]benzodiazepine involving S(N)Ar reaction of 2-nitro-5-fluorobenzoate precursors
-
A synthetic procedure is described for conjugating polyaminoalkyl groups to the pyrrolo[2,1-c][1,4]benzodiazepine pharmacophore in order to alter its characteristic DNA sequence binding preference. To this end S(N)Ar reactions of 2-nitro-5-fluorobenzoate
- Matsumoto, Kiyoshi,Iida, Hirokazu,Lown, J. William
-
p. 1015 - 1020
(2007/10/03)
-
- Preferred secondary structures as a possible driving force for macrocyclization
-
The purpose of the work described in this paper was to explore links that may exist between conformational bias in macrocyclic products and the ease with which they are formed in solid phase S(N)Ar reactions. Solid phase synthesis of compounds 2 proceeds
- Reyes, Samuel,Pattarawarapan, Mookda,Roy, Sudipta,Burgess, Kevin
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p. 9809 - 9818
(2007/10/03)
-
- 3-(3-aryloxyphenyl)-1-(substituted methyl)-s-triazine-2,4,6-oxo or thiotrione herbicidal agents
-
There is provided a 3-(3-aryloxyphenyl)-1-(substituted methyl)-s-triazine-2,4,6-oxo or thiotrione compound having the structural formula I STR1 Further provided are a composition and a method comprising that compound for the control of undesirable plant s
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-
-
- New pyridobenzodiazepine derivatives as potential antipsychotics: Synthesis and neurochemical study
-
The discovery of a new, safe, atypical antipsychotic remains an important challenge. To achieve this goal, a series of N-methylpiperazinopyrido[2,3- b][1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]-benzodiazepines were synthesized. The dopaminergic (D1, D2), serotonergic (5-HT2), and cholinergic (M) affinities, frequently remarked in the action mechanisms of antipsychotic drugs, were determined using their respective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding affinities. Pyridobenzodiazepine derivatives, such as clozapine, were found to be inactive or only weakly effective against apomorphine-mediated stereotypes in rats. In an original and complex behavioral model developed in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypical neuroleptic drugs, 8-chloro-6-(4-methyl-1-piperazinyl)-11H- pyrido[2,3-b][1,4]benzodiazepine (9), 8-methyl-6-(4-methyl-1-piperazinyl)- 11H-pyrido[2,3-b][1,4]benzodiazepine (12), and 5-(4-methyl-1-piperazinyl)- 11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of the behavioral characteristics previously described for neuroleptics. Their neurochemical profiles, particularly their 5-HT2/D2 pK(i) ratios, were compatible with an atypical antipsychotic effect. These compounds were selected for further investigation. The proposed modulations could lead to new possibilities for the pharmacochemistry of diarylazepines.
- Liegeois,Bruhwyler,Damas,Thuy Phuong Nguyen,Chleide,Mercier,Rogister,Delarge
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p. 2107 - 2114
(2007/10/02)
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- SYNTHESIS AND DNA CROSSLINKING ABILITY OF A DIMERIC ANTHRAMYCIN ANALOG
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Linked analogs of the DNA binding antibiotic anthramycin are made via nucleophilic aromatic substitution followed by reduction-cyclization.The linked compounds protect DNA from restriction endonucleases and reversibly crosslink DNA.
- Farmer, J.Dean,Rudnicki, Suzanne M.,Suggs, J.William
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p. 5105 - 5108
(2007/10/02)
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