- Design, synthesis, and biological evaluation of m-amidophenol derivatives as a new class of antitubercular agents
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A series of m-amidophenol derivatives (6a-6l, 7a-7q, 9a, 9b, 12a-12c, 14 and 15) were designed and synthesized. Their antitubercular activities were evaluated in vitro against M. tuberculosis strains H37Ra and H37Rv and clinically isolated multidrug-resistant M. tuberculosis strains. Ten compounds displayed minimal inhibitory concentrations (MICs) against M. tuberculosis H37Ra below 2.5 μg mL?1 and 6g was the most active compound (MIC = 0.625 μg mL?1). Compounds 6g and 7a also showed potent inhibitory activity against M. tuberculosis H37Rv (MIC = 0.39 μg mL?1) and several clinically isolated multidrug-resistant M. tuberculosis strains (MIC = 0.39-3.125 μg mL?1). The compounds did not show inhibitory activity against normal Gram-positive and Gram-negative bacteria. They exhibited low cytotoxicity against HepG2 and RAW264.7 cell lines. The results demonstrated m-amidophenol as an attractive scaffold for the development of new antitubercular agents.
- Zhang, Niu-niu,Liu, Zhi-yong,Liang, Jie,Tang, Yun-xiang,Qian, Lu,Gao, Ya-min,Zhang, Tian-Yu,Zhang, Tian-yu,Yan, Ming
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supporting information
p. 1293 - 1304
(2018/08/28)
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- UREA DERIVATIVES USEFUL AS KINASE INHIBITORS
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There are provided compounds of formula I, wherein R1, R1A, R1C to R1E, Ra, Rb, X1, E and G have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.
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Page/Page column 164
(2015/07/07)
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- Preparation of new alkyne-modified ansamitocins by mutasynthesis
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The preparation of alkyne-modified ansamitocins by mutasynthetic supplementation of Actinosynnema pretiosum mutants with alkyne-substituted aminobenzoic acids is described. This modification paved the way to introduce a thiol linker by Huisgen-type cycloaddition which can principally be utilized to create tumor targeting conjugates. In bioactivity tests, only those new ansamitocin derivatives showed strong antiproliferative activity that bear an ester side chain at C-3.
- Harmrolfs, Kirsten,Mancuso, Lena,Drung, Binia,Sasse, Florenz,Kirschning, Andreas
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supporting information
p. 535 - 543
(2014/04/17)
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- Bioreduction of aryl azides during mutasynthesis of new ansamitocins
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Supplementing a culture of a mutant strain of Actinosynnema pretiosum that is unable to biosynthesize aminohydroxy benzoic acid (AHBA), with 3-azido-5-hydroxy-benzoic acid and 3-azido-5-amino-benzoic acid, unexpectedly yielded anilino ansamitocins instead
- Mancuso, Lena,Juerjens, Gerrit,Hermane, Jekaterina,Harmrolfs, Kirsten,Eichner, Simone,Fohrer, Joerg,Collisi, Wera,Sasse, Florenz,Kirschning, Andreas
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supporting information
p. 4442 - 4445
(2013/09/24)
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- QUINAZOLINONE DERIVATIVES HAVING B-RAF INHIBITORY ACTIVITY
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The invention relates to chemical compounds of the formula (I) or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 12
(2009/07/17)
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- Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C
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Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC δ C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([3H]PDBu) from PKC α and δ at Ki values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time, that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.
- Af Genn?s, Gustav Boije,Talman, Virpi,Aitio, Olli,Ekokoski, Elina,Finel, Moshe,Tuominen, Raimo K.,Yli-Kauhaluoma, Jari
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supporting information; experimental part
p. 3969 - 3981
(2010/01/16)
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- Macrocyclic Compounds Useful as Bace Inhibitors
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The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, the number of ring atoms included in the macrocyclic ring being 14, 15, 16 or 17, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 36
(2008/12/05)
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- MACROCYCLIC COMPOUNDS USEFUL AS BACE INHIBITORS
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The invention relates to novel macrocyclic compounds of the Formula (I) in which all of the variables are as defined in the specification, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 29-30
(2008/06/13)
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- MACROCYCLIC COMPOUNDS USEFUL AS BACE INHIBITORS
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The invention relates to novel macrocyclic compounds of the formula (I), in which all of the variables are as defined in the specification, in free base form or in acid addition salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 65
(2008/06/13)
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- NK-1 AND SEROTONIN TRANSPORTER INHIBITORS
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The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating disorders associated with an excess or imbalance of tachykinins or serotonin or both.
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Page/Page column 85
(2010/11/28)
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- A generic building block for C- and N-terminal protein-labeling and protein-immobilization
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Expressed protein ligation (EPL) and bioconjugation based on the maleimide group (MIC-conjugation) provide powerful tools for protein modification. In the light of the importance of site-selectively modified proteins for the study of protein function, a f
- Watzke, Anja,Gutierrez-Rodriguez, Marta,Koehn, Maja,Wacker, Ron,Schroeder, Hendrik,Breinbauer, Rolf,Kuhlmann, Juergen,Alexandrov, Kirill,Niemeyer, Christof M.,Goody, Roger S.,Waldmann, Herbert
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p. 6288 - 6306
(2007/10/03)
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- PHENYL-SULFAMATES AS AROMATASE INHIBITORS
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There is provided a compound of Formula (I) wherein X, Y and Z are each independently of each other an optional linker group; R, is a ring system; R2 is selected from hydrocarbyl groups, oxyhydrocarbyl groups, cyano (CN), nitro (-NO2) and halogens; R3 and R4 are independently selected from H and hydrocarbyl, ring A and B are independently optionally further substituted.
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Page/Page column 69-70
(2008/06/13)
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- Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
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Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-α-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.
- Parlow, John J.,Case, Brenda L.,Dice, Thomas A.,Fenton, Ricky L.,Hayes, Michael J.,Jones, Darin E.,Neumann, William L.,Wood, Rhonda S.,Lachance, Rhonda M.,Girard, Thomas J.,Nicholson, Nancy S.,Clare, Michael,Stegeman, Roderick A.,Stevens, Anna M.,Stallings, William C.,Kurumbail, Ravi G.,South, Michael S.
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p. 4050 - 4062
(2007/10/03)
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- Pyrimidin derivatives
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The invention relates to new pharmaceutically active compounds which are are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists, compositions containing them and processes for their preparation.
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- Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
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This invention provides novel radiopharmaceuticals that are radiolabeled cyclic compounds containing carbocyclic or heterocyclic ring systems which act as antagonists of the platelet glycoprotein IIb/IIIa complex; to methods of using said radiopharmaceuticals as imaging agents for the diagnosis of arterial and venous thrombi; to novel reagents for the preparation of said radiopharmaceuticals; and to kits comprising said reagents.
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- Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design
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A series of 94 benzoic acid derivatives was synthesized and tested for its ability to inhibit influenza neuraminidase. The enzyme-inhibitor complex structure was determined by X-ray crystallographic analysis for compounds which inhibited the enzyme. The most potent compound tested in vitro, 5 (4- (acetylamino)-3-guanidinobenzoic acid), had an IC50 = 2.5 x 10-6 M against N9 neuraminidase. Compound 5 was oriented in the active site of the neuraminidase in a manner that was not predicted from the reported active site binding of GANA (4) with neuraminidase. In a mouse model of influenza, 5 did not protect the mice from weight loss due to the influenza virus when dosed intranasally.
- Chand, Pooran,Babu, Yarlagadda S.,Bantia, Shanta,Chu, Naiming,Cole, L. Brent,Kotian, Pravin L.,Laver, W. Graeme,Montgomery, John A.,Pathak, Ved P.,Petty, Sandra L.,Shrout, David P.,Walsh, David A.,Walsh, Gerald M.
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p. 4030 - 4052
(2007/10/03)
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