- Discovery of [1,2,4]triazole derivatives as new metallo-β-lactamase inhibitors
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The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.
- Yuan, Chen,Yan, Jie,Song, Chen,Yang, Fan,Li, Chao,Wang, Cheng,Su, Huiling,Chen, Wei,Wang, Lijiao,Wang, Zhouyu,Qian, Shan,Yang, Lingling
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- Green synthesis of benzamide-dioxoisoindoline derivatives and assessment of their radical scavenging activity – Experimental and theoretical approach
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A series of benzamide-dioxoisoindoline derivatives 3 was obtained, starting from phthalic anhydride and different benzoyl hydrazides 2, by ultrasound irradiation in water as solvent and without any catalyst. Five obtained compounds have been reported in this study for the first time and crystal structure of compound 3h was determined. All compounds were subjected to experimental determination of their antioxidative potential. DPPH test revealed that newly synthesized phenolic compounds 3d, 3e, and 3j are the best antioxidants. Additionally, probable radical scavenging pathway was analysed for reactions of the most active compounds and some radicals that can be found in living cells.
- Bogdanovi?, Goran A.,Milovanovi?, Vesna M.,Novakovi?, Sla?ana,Petrovi?, Vladimir P.,Petrovi?, Zorica D.,Simijonovi?, Du?ica
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- Synthesis and bioactivity of sulfide derivatives containing 1,3,4-oxadiazole and pyridine
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A series of novel sulfide derivatives containing 1,3,4-oxadiazole and pyridine were synthesized, characterized, and tested for their antibacterial activity against tobacco bacterial wilt and rice bacterial blight and for insecticidal activity toward diamondback moth. The results showed that some compounds had good insecticidal and bactericidal activity, e.g., the activities of compounds 6e and 6g–6j toward tobacco bacterial wilt were much better than those of commercial thiodiazole-copper, and some of the synthesized compounds possessed good insecticidal activity against Plutella xylostella. Compounds 6d, 6h, 6j, 6l, 6p, 6r, and 6p displayed over 93% activity at 500 mg L? 1.
- Yu, Gang,Chen, Shunhong,He, Feng,Luo, Dexia,Zhang, Yu,Wu, Jian
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p. 1075 - 1085
(2019/09/10)
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- TBSOTf-promoted versatile N-formylation using DMF at room temperature
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Hydrazides and amines were N-formylated by DMF in the presence of tert-butyldimethylsilyl triflate (TBSOTf) at room temperature, in good to excellent yields.
- Sakurai, Masayoshi,Kawakami, Rina,Kihara, Nobuhiro
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supporting information
p. 1291 - 1294
(2019/04/10)
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- Design, synthesis, insecticidal activity and 3D-QSR study for novel trifluoromethyl pyridine derivatives containing an 1,3,4-oxadiazole moiety
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A series of trifluoromethyl pyridine derivatives containing 1,3,4-oxadiazole moiety was designed, synthesized and bio-assayed for their insecticidal activity. The result of bio-assays indicated the synthesized compounds exhibited good insecticidal activity against Mythimna separata and Plutella xylostella, most of the title compounds show 100% insecticidal activity at 500 mg L-1 and >80% activity at 250 mg L-1 against the two pests. Compounds E18 and E27 showed LC50 values of 38.5 and 30.8 mg L-1 against Mythimna separata, respectively, which were close to that of avermectin (29.6 mg L-1); compounds E5, E6, E9, E10, E15, E25, E26, and E27 showed 100% activity at 250 mg L-1, which were better than chlorpyrifos (87%). CoMFA and CoMSIA models with good predictability were proposed, which revealed the electron-withdrawing groups with an appropriate bulk at 2- and 4-positions of benzene ring could enhance insecticidal activity.
- Xu,Wang,Luo,Yu,Guo,Fu,Zhao,Wu
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p. 6306 - 6314
(2018/02/19)
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- Tyrosinase and carbonic anhydrase enzymes inhibition studies of vanadium(V) complexes
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Present study endeavors synthesis of series of vanadium(V) hydrazide complexes and its enzyme inhibition studies. Octahedral structure of complexes has been evaluated previously using conductance measurements, spectroscopic techniques involving IR,1H-NMR and13C-NMR, elemental analysis using CHN technique. Complexes 1c-12c have found to exhibit monomeric form with hydrazides behaving as bidentate ligand coordinating by their N and O atoms, while two oxygen atoms have also been found to show attachment with the metal centre. This study includes activity of vanadium(V) complexes to inhibit tyrosinase and carbonic anhydrase enzymes. For inhibition of carbonic anhydrase all, while for tyrosinase most of the hydrazide ligands were found to be inactive. Vanadium(V) complexes with these hydrazides have found to bear variable degree of carbonic anhydrase and tyrosinase inhibition activity. Some of the vanadium(V) hydrazide complexes were found to be potent inhibitors of tyrosinase enzyme and carbonic anhydrase as well.
- Sultan, Sadaf,Ashiq, Uzma,Jamal, Rifat Ara,Mahroof-Tahir, Mohammad,Ahmad, Rao Saeed,Shaikh, Zara
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- Microwave assisted synthesis and evaluation of some substituted 1,3,4-oxadiazoles as free radical scavenger
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A series of 5-(4-substituted phenyl)-1,3,4-oxadiazoles (4a-h) were prepared from 4-substituted benzoic acid hydrazides (3a-h). Structures of the synthesized compounds were confirmed on the basis of IR, 13C NMR, Mass spectral methods and elemental analysis. The compounds were screened for antioxidant activities using hydrogen peroxide scavenging method comparing with ascorbic acid as standard antioxidant. The results reveal that the compounds possess significant free radical scavenging activities. It is recommended that these compounds might be used in future to generate derivatives for emerging free radical scavenger.
- Upadhyay, Prabhat Kumar,Mishra, Pradeep
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p. 661 - 666
(2020/07/02)
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- SPIROCYCLIC COMPOUNDS
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Disclosed herein are spirocyclic compounds, together with pharmaceutical compositions and methods of ameliorating and/or treating a cancer described herein with one or more of the compounds described herein.
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Paragraph 0216
(2018/04/21)
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- Synthesis of novel 5-(aroylhydrazinocarbonyl)escitalopram as cholinesterase inhibitors
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A novel series of 5-(aroylhydrazinocarbonyl)escitalopram (58–84) have been designed, synthesized and tested for their inhibitory potential against cholinesterases. 3-Chlorobenzoyl- (71) was found to be the most potent compound of this series having IC50 1.80 ± 0.11 μM for acetylcholinesterase (AChE) inhibition. For the butyrylcholinesterase (BChE) inhibition, 2-bromobenzoyl- (76) was the most active compound of the series with IC50 2.11 ± 0.31 μM. Structure-activity relationship illustrated that mild electron donating groups enhanced enzyme inhibition while electron withdrawing groups reduced the inhibition except o-NO2. However, size and position of the substituents affected enzyme inhibitions.. In docking study of AChE, the ligands 71, 72 and 76 showed the scores of 5874, 5756 and 5666 and ACE of ?64.92,-203.25 and ?140.29 kcal/mol, respectively. In case of BChE, ligands 71, 76 and 81 depicted high scores 6016, 6150 and 5994 with ACE values ?170.91, ?256.84 and ?235.97 kcal/mol, respectively.
- Nisa, Mehr-un,Munawar, Munawar A.,Iqbal, Amber,Ahmed, Asrar,Ashraf, Muhammad,Gardener, Qurra-tul-Ann A.,Khan, Misbahul A.
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supporting information
p. 396 - 406
(2017/07/10)
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- Synthesis of novel triazoles and a tetrazole of escitalopram as cholinesterase inhibitors
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A novel serie of escitalopram triazoles (60-88) and a tetrazole (89) have been synthesized and subjected to a study to establish the inhibitory potential of these compounds toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Some selectivity in inhibition has been observed. The 4-chlorophenyl- (75, IC50, 6.71 ± 0.25 μM) and 2-methylphenyl- (70, IC50, 9.52 ± 0.23 μM) escitalopram triazole derivatives depicted high AChE inhibition, while 2-fluorophenyl- (76, IC50 = 4.52 ± 0.17 μM) and 4-fluorophenyl- (78, IC50 = 5.31 ± 0.43 μM) have found to be excellent BChE inhibitors. It has also been observed that ortho, meta and para substituted electron donating groups increase the inhibition, while electron withdrawing groups reduce the inhibition. Docking analyses of inhibitors with AChE have depicted the binding energies for 70 and 75 as ΔGbind -6.42 and -6.93 kcal/mol, respectively, while ligands 76 and 78 have shown the binding affinity ΔGbind -9.04 and -8.51 kcal/mol, respectively, for BChE.
- Mehr-Un-Nisa,Munawar, Munawar A.,Chattha, Fauzia A.,Kousar, Samina,Munir, Jawaria,Ismail, Tayaba,Ashraf, Muhammad,Khan, Misbahul A.
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supporting information
p. 6014 - 6024
(2015/11/11)
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- Compound
-
Disclosed is a novel organic semiconductor material which has a twisted quaterphenylene skeleton as a central unit and simultaneously possesses a skeleton having an electron-transporting property and a skeleton having a hole-transporting property at the terminals of the quaterphenylene skeleton. Specifically, the organic semiconductor material has a [1,1′:2′,1″:2″,1′″]quaterphenyl-4-4′″-diyl group, and one of the terminals of the [1,1′:2′,1″:2″,1′″]quaterphenyl-4-4′″-diyl group is bonded to a skeleton having an electron-transporting property such as a benzoxazole group or an oxadiazole group. A skeleton having a hole-transporting property such as diarylamino group is introduced at the other terminal. This structure allows the formation of a compound having a bipolar property, a high molecular weight, an excellent thermal stability, a large band gap, and high triplet excitation energy.
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-
Paragraph 0492-0494
(2016/10/09)
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- Chemistry and antioxidant properties of titanium(IV) complexes
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Abstract The synthesis of titanium(IV) complexes with biologically active hydrazide ligands has been carried out. The complexes were characterized by spectroscopic methods (IR, 1H NMR and 13C NMR), elemental analysis and conductivity studies. These studies suggest bidentate coordination of the ligands through carbonyl oxygen and primary amine nitrogen, resulting in octahedral geometries. Hydrazides with pyridyl substituents displayed 1:2 metal-to-ligand ratio, and hydrazides with imino substituents exhibited 1:3 metal-to-ligand ratio resulting in an outer sphere complex. The remaining complexes displayed inner sphere coordination with 1:1 metal-to-ligand ratio. These complexes exhibit varying degrees of radical scavenging properties against DPPH, superoxide and nitric oxide free radicals. The free ligands showed inhibition against DPPH but were inactive against superoxide and nitric oxide free radicals. The structure-activity relationships of the complexes are discussed.
- Shaikh, Zara,Ashiq, Uzma,Jamal, Rifat Ara,Mahroof-Tahir, Mohammad,Shamshad, Bushra,Sultan, Sadaf
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p. 665 - 671
(2015/08/06)
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- Studies on chemistry, spectroscopy and antioxidant activities of chromium(III)-hydrazide complexes
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Acid hydrazides are vital chemical entities due to their biological activities. Upon complexation with certain metal ions, their biological activities are known to be positively enhanced. The present work describes the synthesis of Cr(III)-hydrazide complexes, and their structural, spectroscopic and antioxidant properties to reveal their chemistry and biochemistry. Physical (magnetic moment, conductivity measurements), analytical (C, H, N and Cr analysis) and spectral (EI-Mass, FTIR) techniques are used for the characterization of synthesized compounds. All Cr(III)-hydrazide complexes exhibit octahedral geometry with general formula [Cr(L)2(H2O)2]Cl3. In these complexes, the hydrazide ligands are coordinated via carbonyl oxygen and terminal amino nitrogen in a bidentate fashion. All Cr(III)-hydrazide complexes were screened for in vitro diphenyldipicryl hydrazine (DPPH), superoxide dismutase and nitric oxide radical scavenging activities. Majority of the Cr(III)-hydrazide complexes were found to be more potent scavengers than their uncoordinated hydrazide ligands. This study demonstrates an interesting structure-activity relationship (SAR) which is presented here.
- Shamshad, Bushra,Jamal, Rifat A.,Ashiqa, Uzma,Mahrooof-Tahirb, Mohammad,Shaikha, Zara,Sultana, Sadaf,Khanc, Khalid M.
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p. 798 - 806
(2015/12/01)
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- Rhodium-catalyzed C-H activation of hydrazines leads to isoquinolones with tunable aggregation-induced emission properties
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Using an internally oxidizing directing group (DG) strategy, we report a RhIII-catalyzed synthesis of isoquinolones via C-H activation/annulation of benzoylhydrazines and alkynes. Tunable double cascade cyclization of benzoylhydrazines with two equivalents of alkynes led to tetracyclic amides. These N-heterocycles demonstrated adjustable AIE properties.
- Yu, Bole,Chen, Ying,Hong, Mei,Duan, Pingping,Gan, Shifeng,Chao, Hui,Zhao, Zujin,Zhao, Jing
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supporting information
p. 14365 - 14368
(2015/09/21)
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- 5-Nitro-2-furfuriliden derivatives as potential anti-Trypanosoma cruzi agents: Design, synthesis, bioactivity evaluation, cytotoxicity and exploratory data analysis
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The anti-Trypanosoma cruzi activity of 5-nitro-2-furfuriliden derivatives as well as the cytotoxicity of these compounds on J774 macrophages cell line and FN1 human fibroblast cells were investigated in this study. The most active compounds of series I and II were 4-butyl-[N′-(5-nitrofuran-2-yl) methylene] benzidrazide (3g; IC50 = 1.05 μM ± 0.07) and 3-acetyl-5-(4-butylphenyl)-2-(5-nitrofuran-2-yl)-2,3-dihydro,1,3,4-oxadiazole (4g; IC50 = 8.27 μM ± 0.42), respectively. Also, compound 3g was more active than the standard drugs, benznidazole (IC50 = 22.69 μM ± 1.96) and nifurtimox (IC50 = 3.78 μM ± 0.10). Regarding the cytotoxicity assay, the 3g compound presented IC 50 value of 28.05 μM (SI = 26.71) against J774 cells. For the FN1 fibroblast assay, 3g showed IC50 value of 98 μM (SI = 93.33). On the other hand, compound 4g presented a cytotoxicity value on J774 cells higher than 400 μM (SI >48), and for the FN1 cells its IC50 value was 186 μM (SI = 22.49). Moreover, an exploratory data analysis, which comprises hierarchical cluster (HCA) and principal component analysis (PCA), was carried out and the findings were complementary. The molecular properties that most influenced the compounds' grouping were C log P and total dipole moment, pointing out the need of a lipophilic/hydrophilic balance in the designing of novel potential anti-T. cruzi molecules.
- Palace-Berl, Fanny,Jorge, Salom?o Dória,Pasqualoto, Kerly Fernanda Mesquita,Ferreira, Adilson Kleber,Maria, Durvanei Augusto,Zorzi, Rodrigo Rocha,De Sá Bortolozzo, Leandro,Lindoso, José ?ngelo Lauletta,Tavares, Leoberto Costa
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p. 5395 - 5406
(2013/09/02)
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- Dual IGF-1R/SRC inhibitors based on a N′-aroyl-2-(1H-indol-3-yl)-2- oxoacetohydrazide structure
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The N′-aroyl-2-(1H-indol-3-yl)-2-oxoacetohydrazide motif was identified as a novel scaffold for the development of kinase inhibitors. Derivatives with a biphenyl element attached to the hydrazide structure proved to be submicromolar dual inhibitors of the cancer-related kinases IGF-1R and SRC. One of the most potent kinase inhibitors of the series produced a selective growth inhibition in a panel of cultivated cancer cell lines.
- Schmidt, Stefanie,Preu, Lutz,Lemcke, Thomas,Totzke, Frank,Sch?chtele, Christoph,Kubbutat, Michael H.G.,Kunick, Conrad
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scheme or table
p. 2759 - 2769
(2011/07/08)
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- Polymers with carbazole-oxadiazole side chains as ambipolar hosts for phosphorescent light-emitting diodes
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Polymethacrylates, polystyrenes, and polynorbornenes bearing 2-(3-(carbazol-9-yl)phenyl)-5-phenyl-1,3,4-oxadiazole, 2-(4-(carbazol-9-yl) phenyl)-5-phenyl-1,3,4-oxadiazole, 2-(3,5-di(carbazol-9-yl)phenyl)-5-phenyl-1,3, 4-oxadiazole) groups linked to the po
- Zhang, Yadong,Zuniga, Carlos,Kim, Sung-Jin,Cai, Dengke,Barlow, Stephen,Salman, Seyhan,Coropceanu, Veaceslav,Bredas, Jean-Luc,Kippelen, Bernard,Marder, Seth
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experimental part
p. 4002 - 4015
(2012/04/11)
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- Synthesis, molecular modeling and preliminary biological evaluation of a set of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole as potential antibacterial, anti-Trypanosoma cruzi and antifungal agents
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A series of 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives was synthesized and their activity screened in vitro against Staphylococcus aureus, Trypanosoma cruzi, and Candida albicans. The bioactivity was expressed as minimum inhibitory concentration (MIC) for S. aureus strains, and as fifty-percent inhibitory concentration (IC50) of parasite population growth for T. cruzi. A molecular modeling approach was performed to establish qualitative relationships regarding the biological data and the compounds' physicochemical properties. The 5-(4-OC4H9Ph, 5μ), and 5-(4-CO2CH3Ph, 5o) derivatives were the most active compounds for S. aureus ATCC 25923 (MIC = 1.95 -1.25 μg/mL) and T. cruzi (IC50 = 7.91 μM), respectively. Also, a preliminary evaluation against C. albicans involving some compounds was performed and the 5-(4-CH 3Ph, 5e) derivative was the most active compound (MIC = 3.28-2.95 μg/mL). In this preliminary study, all synthesized 3-acetyl-2,5- disubstituted-2,3-dihydro-1,3,4-oxadiazole derivatives were active against all microorganisms tested.
- Ishii, Marina,Jorge, Salom?o Dória,De Oliveira, Alex Alfredo,Palace-Berl, Fanny,Sonehara, Ieda Yuriko,Pasqualoto, Kerly Fernanda Mesquita,Tavares, Leoberto Costa
-
experimental part
p. 6292 - 6301
(2011/12/02)
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- 17O NMR studies of substituted 1,3,4-oxadiazoles
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Three series of substituted 1,3,4-oxadiazoles were studied by 17O NMR spectroscopy. Chemical shifts values were correlated with empirical Hammett parameters as well as calculated bond lengths and chemical shielding values.
- Gierczyk, Blazej,Zalas, MacIej,Kazmierczak, Marcin,Grajewski, Jakub,Pankiewicz, Radoslaw,Wyrzykiewicz, Bozena
-
scheme or table
p. 648 - 654
(2012/01/06)
-
- Organic Semiconductor Material and Light-Emitting Element, Light-Emitting Device, Lighting System, and Electronic Device Using the Same
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Disclosed is a novel organic semiconductor material which has a twisted quaterphenylene skeleton as a central unit and simultaneously possesses a skeleton having an electron-transporting property and a skeleton having a hole-transporting property at the t
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-
-
- POLYMERIZABLE AMBIPOLAR HOSTS FOR PHOSPHORESCENT GUEST EMITTERS
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The inventions describe disclosed and described herein relate to polymerizable ambipolar monomers, useful for making polymer or copolymer host materials for guest phosphorescent metal complexes, which together can form emission layers of organic light emitting diodes (OLEDs). Methods of making the ambipolar monomers are also described. Formula (I) wherein at least one of the R1, R2 and R3 groups is an optionally substituted carbazole group.
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Page/Page column 42
(2011/01/12)
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- Design, synthesis, antimicrobial activity and molecular modeling studies of novel benzofuroxan derivatives against Staphylococcus aureus
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Molecular modification is a quite promising strategy in the design and development of drug analogs with better bioavailability, higher intrinsic activity and less toxicity. In the search of new leads with potential antimicrobial activity, a new series of 14 4-substituted [N′-(benzofuroxan-5-yl)methylene]benzohydrazides, nifuroxazide derivatives, were synthesized and tested against standard and multidrug-resistant Staphylococcus aureus strains. The selection of the substituent groups was based on physicochemical properties, such as hydrophobicity and electronic effect. These properties were also evaluated through the lipophilic and electrostatic potential maps, respectively, considering the compounds with better biological profile. Twelve compounds exhibited similar bacteriostatic activity against standard and multidrug-resistant strains. The most active compound was the 4-CF3 substituted derivative, which presented a minimum inhibitory concentration (MIC) value of 14.6-13.1 μg/mL, and a Clog P value of 1.87. The results highlight the benzofuroxan derivatives as potential leads for designing new future antimicrobial drug candidates.
- Jorge, Salomao Doria,Masunari, Andrea,Rangel-Yagui, Carlota Oliveira,Pasqualoto, Kerly Fernanda Mesquita,Tavares, Leoberto Costa
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experimental part
p. 3028 - 3036
(2009/09/08)
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- A new class of nifuroxazide analogues: Synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus
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Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been an increasing problem worldwide since the initial reports over 40 years ago. To examine new drug leads with potential antibacterial activities, 14 p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized, and tested against standard and multidrug-resistant S. aureus strains by serial dilution tests. All compounds exhibited significant bacteriostatic activity and some of them also showed bactericidal activity. The results confirmed the potential of this class of compounds as an alternative for the development of selective antimicrobial agents.
- Masunari, Andrea,Tavares, Leoberto Costa
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p. 4229 - 4236
(2008/03/13)
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- Molecular wires comprising π-extended ethynyl- and butadiynyl-2,5- diphenyl-1,3,4-oxadiazole derivatives: Synthesis, redox, structural, and optoelectronic properties
-
2,5-Diphenyl-1,3,4-oxadiazole (OXD) derivatives with terminal ethynyl- (4a,b) and butadiynyl-(8a,b) substituents have been synthesized in high yields. 2-Methyl-3,5-hexadiyn-2-ol has not been exploited previously in the synthesis of terminal butadiynes. Cr
- Wang, Changsheng,Palsson, Lars-Olof,Batsanov, Andrei S.,Bryce, Martin R.
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p. 3789 - 3799
(2007/10/03)
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- The synthesis and fungicidal activities of 2,6-bis[(3-aryl)-s-triazolo[3,4- b]-[1,3,4]thiadiazole-6-yl]pyridines
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In search of better bioactive compounds, a series of novel 2,6-bis[(3-aryl)-s-triazolo[3,4-b]-[1,3,4]thiadiazole-6-yl]pyridines 2 were synthesized in high yields by the cyclization of 3-aryl-4-amino-5-mercapto-1, 2, 4-triazoles 1 with 2,6-pyridine dicarboxylic acid. 2 exhibited good fungicidal activities against Cerospora beticola sacc. Copyright Taylor & Francis Group, LLC.
- Li, Dejiang,Long, Deqing,Fu, Heqing
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p. 2079 - 2087
(2007/10/03)
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- Compositions and methods for treating cancer
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The invention features compositions and methods for treating or alleviating a symptom of cancer. The compositions and methods of the invention direct supra-lethal doses of radiation, called Hot-Spots, to virtually all cancer cell types.
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Page/Page column 22-23
(2008/06/13)
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- NIACIN RECEPTOR AGONISTS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
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The present invention encompasses compounds of Formula (I); as well as pharmaceutically acceptable salts and hydrates thereof, that are useful for treating dyslipidemias. Pharmaceutical compositions and methods of use are also included.
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Page/Page column 61
(2010/11/08)
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- HETEROARYL SUBSTITUTED BIPHENYL DERIVATIVES AS P38 KINASE INHIBITORS
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Compounds of formula (I) are inhibitors of p38 kinase and are useful in the treatment of conditions or disease states mediated by p38 kinase activity or mediated by cytokines produced by the activity of p38.
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Page/Page column 25
(2010/02/07)
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- 3-D QSAR analysis of inhibition of murine soluble epoxide hydrolase (MsEH) by benzoylureas, arylureas, and their analogues
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Two hundred and seventy-one compounds including benzoylureas, arylureas and related compounds were assayed using recombinant murine soluble epoxide hydrolase (MsEH) produced from a baculovirus expression system. Among all the insect growth regulators assayed, 18 benzoylphenylurea congeners showed weak activity against MsEH. Newly synthesized cyclohexylphenylurea, 1-benzyl-3-phenylurea, and 1,3-dibenzylurea analogues were rather potent. The introduction of a methyl group at the para-position of the phenyl ring of cyclohexylphenylurea enhanced the activity 6-fold, though similar substituent effects were not seen for any of the benzoylphenylureas. The activities of these compounds, including several previously reported compounds, such as dicyclohexylurea, diphenylurea, and their related analogues (Morisseau et al., Proc. Natl. Acad. Sci., 1999, 96, 8849), were quantitatively analyzed using comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship (3-D QSAR) method. Both steric and electrostatic factors contributing to variations in the activity were visualized using CoMFA. CoMFA results showed that one side of the cyclohexylurea moiety having a trans-amide conformation (A-ring moiety) is surrounded by large sterically unfavorable fields, while the other side of A-ring moiety and the other cyclohexyl group (B-ring moiety) is encompassed by sterically favored fields. Electrostatically negative fields were scattered around the entire molecule, and a positive field surrounds the carbon of the carbonyl group. Hydrophobic fields were visualized using Kellogg's hydropathic interaction (HINT) in conjunction with CoMFA. Hydrophobically favorable fields appeared beside the 4- and 4'-carbon atoms of the cyclohexyl groups, and hydrophobically unfavorable fields surrounded the urea bridge. The addition of the molecular hydrophobicity, it> /it>, to CoMFA did not improve the correlation significantly. The ligand-binding interactions shown by X-ray crystallographic data were rationalized using the results of the CoMFA and HINT analyses, and the essential physicochemical parameters for the design of new MsEH inhibitors were disclosed. Copyright (C) 2000 Elsevier Science Ltd.
- Nakagawa, Yoshiaki,Wheelock, Craig E.,Morisseau, Christophe,Goodrow, Marvin H.,Hammock, Bruce G.,Hammock, Bruce D.
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p. 2663 - 2673
(2007/10/03)
-