benzofurans and imidazole

The H3 receptor is prominently expressed in neuronal tissues, and H3 antagonists have been proposed as drugs with benefits in disorders of cognition, attention, pain, allergic rhinitis, and obesity. The structure-activity relationships (SAR) of various classes of non-imidazole H3 antagonists are reviewed, along with highlights of functional efficacy in tissue-based and animal disease models.

Topics: Animals; Benzofurans; Histamine Antagonists; Humans; Imidazoles; Receptors, Histamine H3; Structure-Activity Relationship

A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 2-ethyl-imidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or naphthylacyl group, were vital for modulating inhibitory activity. In particular, hybrid compound 31 was found to be the most potent derivative with IC₅₀ values of 0.08-0.55 μM against five strains human tumor cell lines and was found to be more selective against breast carcinoma (MCF-7) and colon carcinoma (SW480) (IC₅₀ values 40.8-fold and 40.1-fold lower than cisplatin (DDP)).

Topics: Antineoplastic Agents; Benzofurans; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Imidazoles; MCF-7 Cells; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Protein Structure, Tertiary; Structure-Activity Relationship; Triazoles

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.

Topics: Benzofurans; Cell Line, Tumor; Cell Survival; Humans; Imidazoles; Melanoma; Naphthols; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thiophenes

The hexaazamacrocycles [28](DBF)(2)N(6) {cyclo[bis(4,6-dimethyldibenzo[b,d]furaniminoethyleneiminoethylene]} and [32](DBF)(2)N(6) {cyclo[bis(4,6-dimethyldibenzo[b,d]furaniminopropyleneiminopropylene]} form stable dinuclear copper(ii) complexes suitable to behave as receptors for several anionic substrates. These two receptors were used to study the binding interactions with several substrates, such as imidazole (Him) and some carboxylates [benzoate (bz(-)), oxalate (ox(2-)), malonate (mal(2-)), phthalate (ph(2-)), isophthalate (iph(2-)), and terephthalate (tph(2-))] by spectrophotometric titrations and EPR spectroscopy in MeOH (or H(2)O):DMSO (1 : 1 v/v) solution. The largest association constant was found for ox(2-) with Cu(2)[32](DBF)(2)N(6)(4+), whereas for the aromatic dicarboxylate anions the binding constants follow the trend ph(2-) > iph(2-) > tph(2-), i.e. decrease with the increase of the distance of the two binding sites of the substrate. On the other hand, the large blue shift of 68 nm observed by addition of Him to Cu(2)[32](DBF)(2)N(6)(4+) points out for the formation of the bridged CuimCu cascade complex, indicating this receptor as a potential sensor for the detection and determination of imidazole in solution. The X-band EPR spectra of the Cu(2)[28](DBF)(2)N(6)(4+) and Cu(2)[32](DBF)(2)N(6)](4+) complexes and the cascade complexes with the substrates, performed in H(2)O:DMSO (1 : 1 v/v) at 5 to 15 K, showed that the CuCu distance is slightly larger than the one found in crystal state and that this distance increases when the substrate is accommodated between the two copper centres. The crystal structure of [Cu(2)[28](DBF)(2)N(6)(ph)(2)]·CH(3)OH was determined by X-ray diffraction and revealed the two copper centres bridged by two ph(2-) anions at a CuCu distance of 5.419(1) Å. Each copper centre is surrounded by three carboxylate oxygen atoms from two phthalate anions and three contiguous nitrogen atoms of the macrocycle in a pseudo octahedral coordination environment.

Topics: Anions; Benzofurans; Carboxylic Acids; Coordination Complexes; Copper; Crystallography, X-Ray; Electron Spin Resonance Spectroscopy; Imidazoles; Macrocyclic Compounds; Molecular Conformation; Spectrophotometry, Ultraviolet

In this study, some aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketones, aryl (3-methyl-benzofuran-2-yl) ketoximes and aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes were synthesised starting from 2-aryloyl-3-methyl-benzofuranes. The structure elucidation of the compounds was performed by IR, 1H-NMR, MASS spectroscopy and elemental analyses. Antifungal activities of the compounds were examined and moderate activity was obtained.

Topics: Antifungal Agents; Azoles; Benzofurans; Candida; Imidazoles; Methylation; Molecular Structure; Oximes; Structure-Activity Relationship

The design, synthesis and biological evaluation of lexitropsins bearing mixed heterocyclic and benzoheterocyclic moieties and tethered to an alpha-bromo acrylic moiety acting as alkylating moiety are reported, and structure-activity relationships determined. With respect to antiproliferative activity against L1210 and K562 cells, compounds 7 and 10 showed the greatest potency, while compounds 4 and 5 exhibit the lowest activity. Among the synthesized compounds 4-12, the derivative 10 was found to be the most potent member of this class and it is 70-fold more active than the bis-pyrrole counterpart 3 against L1210 cell line. In addition, the cytotoxicity of derivatives 5-12 against KB cells and the influence of different glutathione (GSH) concentrations on the cytotoxic effects was also investigated.

Topics: Animals; Antineoplastic Agents, Alkylating; Benzofurans; Drug Screening Assays, Antitumor; Heterocyclic Compounds; Humans; Imidazoles; Mice; Molecular Structure; Netropsin; Pyrazoles; Pyrroles; Structure-Activity Relationship; Thiophenes; Tumor Cells, Cultured

2-aminoethylbenzofurans constitute a new class of H(3) antagonists that are more rotationally constrained than most previously reported H(3) antagonists. They retain high potency at human and rat receptors, with efficient CNS penetration observed in 35. The SAR of the basic amine moiety was compared in three different series of analogues. The greatest potency was found in analogues bearing a 2-methylpyrrolidine, a 2,5-dimethylpyrrolidine, or a 2,6-dimethylpiperidine.

Topics: Amines; Animals; Benzofurans; Central Nervous System; Histamine Antagonists; Humans; Imidazoles; Molecular Structure; Piperidines; Pyrroles; Pyrrolidines; Rats; Receptors, Histamine H3; Structure-Activity Relationship

Certain imidazoline drugs stimulate insulin secretion acutely but their longer term effects on the viability of pancreatic beta-cells are less well characterised. Indeed, some reports have suggested that imidazolines can be toxic to beta-cells while others have reported protective effects against other cytotoxic agents.. In order to address these discrepancies, the effects of two structurally related imidazolines, efaroxan and idazoxan, on the viability of clonal BRIN-BD11 beta-cells, were compared.. BRIN-BD11 cells were exposed to test reagents and their viability monitored by measuring cellular reducing ability and DNA fragmentation. Nitric oxide was measured indirectly via medium nitrite formation.. Efaroxan (up to 100 micro M) did not directly affect BRIN-BD11 cell viability in the absence of other agents and it did not protect these cells against the cytotoxic effects of interleukin-1beta. Indeed, analysis of DNA fragmentation in BRIN-BD11 cells revealed that efaroxan enhanced the level of damage caused by interleukin-1beta. Idazoxan caused a time- and dose-dependent loss of BRIN-BD11 cell viability in the absence of other ligands. This was associated with marked DNA degradation but was not associated with formation of nitric oxide. The effects of idazoxan were insensitive to blockade of alpha(2)-adrenoceptors or 5-HT(1A) (5-hydroxytryptamine; serotonin) receptors.. The results confirm that idazoxan is cytotoxic to beta-cells but show that efaroxan is better tolerated. However, since efaroxan enhanced the cytotoxic effects of interleukin-1beta, it appears that this imidazoline may sensitise BRIN-BD11 cells to the damaging effects of certain cytokines.

Topics: Animals; Benzofurans; Binding Sites; Cell Line; Cell Survival; DNA; DNA Fragmentation; Dose-Response Relationship, Drug; Idazoxan; Imidazoles; Insulin; Insulin Secretion; Interleukin-1; Islets of Langerhans; Nitric Oxide; Time Factors

As a continuing effort to establish the structure and activity relationship in a benzofuran type of angiotensin II antagonist, we synthesized various regioisomers and performed a series of QSAR analyses. The conformational analyses of target isomers were carried out using molecular mechanics and fine-tuned using the information from the NMR NOE experiment. The conformations of compounds with a good binding activity are quite similar to that of DuP753, a prototype of AII antagonist, suggesting that these compounds also bind to the same site of AII receptor. We then studied the compounds with a varied length of the hydroxyl group bearing side chain to find out the optimum distance between the hydroxyl group and the imidazole ring. The CoMFA with these compounds gave acceptable statistical measures (cross-validated r2 and conventional r2 to be 0.881 and 0.974, respectively) and the map was well consistent with the previously proposed pharmacophore.

Topics: Algorithms; Angiotensin Receptor Antagonists; Benzofurans; Binding, Competitive; Drug Design; Humans; Imidazoles; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Protein Binding; Quantitative Structure-Activity Relationship; Tetrazoles

This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate-induced necrosis and on apoptosis induced by low extracellular K+ in cultured cerebellar granule cells. Exposure (30 min) of energy deprived cells to L-glutamate (1-100 microM) caused a concentration-dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) into a reduced formazan product. L-glutamate-induced neurotoxicity (EC50=5 microM) was blocked by the specific NMDA receptor antagonist MK-801 (dizocilpine). Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 microM (EC100) L-glutamate with the rank order (EC50 in microM): antazoline (13)>cirazoline (44)>LSL 61122 [2-styryl-2-imidazoline] (54)>LSL 60101 [2-(2-benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2-(1,4-benzodioxan-6-yl)-4,5-dihydroimidazole](101)>RX82 1002 (2-methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors. Imidazol(ine) drugs and agmatine fully inhibited [3H]-(+)-MK-801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting against L-glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]-(+)-MK-801 binding. In HEK-293 cells transfected to express the NR1-1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage- and concentration-dependent block of glutamate-induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50 of 10-12 microM at 0 mV. It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate-induced necrotic neuronal cell death in vitro and that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore.

Topics: Agmatine; Animals; Antazoline; Benzofurans; Cell Line; Cells, Cultured; Cerebellum; Dioxanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrophysiology; Glutamic Acid; Humans; Idazoxan; Imidazoles; Neuroprotective Agents; Patch-Clamp Techniques; Potassium; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Styrenes

The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B2 formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies.

Topics: Arachidonic Acids; Aspirin; Astrocytes; Benzofurans; Brain Neoplasms; Cell Adhesion; Cell Movement; Enzyme Induction; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; GTP-Binding Proteins; Humans; Imidazoles; Indomethacin; Lysine; Models, Biological; Neoplasm Proteins; Neoplastic Stem Cells; Oligodendroglia; Pentanoic Acids; Phenotype; Pyridines; RNA, Messenger; RNA, Neoplasm; Signal Transduction; Thromboxane B2; Thromboxane-A Synthase; Tumor Cells, Cultured

The effects of thromboxane synthesis inhibitors (imidazole and U 63557A; Upjohn) and the cyclooxygenase inhibitor, mefenamic acid, on jejunal capillary filtration coefficients (Kfc) were determined in dogs before and during the presence of predigested food in the jejunal lumen. The jejunal Kfc increased significantly soon after the placement of a predigested test food containing all major constituents of diet. The Kfc remained elevated as long as the food was present in the lumen (15 min). Mefenamic acid (10 mg/kg iv) did not significantly alter resting jejunal Kfc or alter the food-induced increase in Kfc. Imidazole (5.0 mg/min ia) or U 63557A (5.0 mg/kg iv) per se significantly increased jejunal Kfc. Placement of digested food further increased the Kfc to levels significantly higher than those observed before administration of the two thromboxane synthase inhibitors. Production of thromboxane B2 by jejunal tissue was significantly reduced and 6-ketoprostaglandin F1 alpha (the stable hydrolysis product of prostacyclin) production was significantly increased after administration of U 63557A. Our study indicates that the relative production of endogenous thromboxanes and other prostanoids modulates jejunal capillary exchange capacity in the absence or presence of digested food in the jejunal lumen.

Topics: Animals; Benzofurans; Capillary Permeability; Dogs; Female; Food; Imidazoles; Intestinal Absorption; Jejunum; Male; Mefenamic Acid; Regional Blood Flow; Thromboxane-A Synthase; Venous Pressure

The myotropic activities of PAF-acether, leukotriene B4, leukotriene D4 and histamine were compared on superfused guinea-pig lung parenchymal strip and were shown to have the following order of potency: PAF-acether greater than LTD4 greater than LTB4 greater than histamine. The contractile response of the lung parenchyma to PAF-acether was inhibited by aspirin, imidazole and OKY-046, which suggested that thromboxane A2 might play a mediator role in PAF-induced contractions. Neither an antagonist of leukotriene D4, FPL-55712, nor an antihistamine, mepyramine, had any effect on PAF contractions. The activity of a novel antagonist of PAF-acether, BN 52021, was also studied on superfused lung parenchyma contracted by histamine, leukotriene B4, leukotriene D4 and PAF-acether. This compound was without effect on the histamine response but it slightly reduced the contractions elicited by leukotriene D4 and potentiated those by leukotriene B4. BN 52021 (7.1 X 10(-6) M) inhibited by 63% the contraction induced by 5.7 X 10(-13) M PAF-acether and by 52% that induced by 5.7 X 10(-10) M PAF-acether and kadsurenone (8.4 X 10(-6) M), another PAF-acether antagonist, inhibited the same PAF-induced contractions by 75% and 20% respectively.

Topics: Animals; Aspirin; Benzofurans; Chromones; Diterpenes; Ginkgolides; Guinea Pigs; Histamine; Imidazoles; Lactones; Leukotriene B4; Lignans; Lung; Male; Methacrylates; Muscle Contraction; Muscle, Smooth; Plant Extracts; Platelet Activating Factor; Prostaglandin Antagonists; Pyrilamine; SRS-A

Indirect methods for the detection of singlet oxygen in dye-sensitized photooxidation based on its interception by some singlet oxygen acceptors in aqueous and micellar solutions are discussed. Mechanistic aspects and some applications of a very sensitive method using p-nitrosodimethylaniline in the presence of imidazole (RNO + imidazole method) are also treated. The technique of competition kinetics with a singlet oxygen quencher N-3 which can serve for the determination of the role of singlet oxygen is discussed as well. Such competition with tryptophan and guanosine shows that these substrates react exclusively or predominantly via the singlet oxygen mechanism in the presence of hematoporphyrin as sensitizing dye.

Topics: Benzofurans; Coloring Agents; Free Radicals; Hematoporphyrins; Imidazoles; Kinetics; Micelles; Nitrogen Oxides; Nitroso Compounds; Oxygen; Photochemistry; Singlet Oxygen; Solutions; Water

The effects of imidazole and U-63557A (Upjohn), inhibitors of thromboxane synthesis, on food-induced changes in intestinal blood flow and oxygen uptake were determined in the jejunum of anesthetized dogs. Intra-arterial (5.0 mg/min ia) infusions of imidazole had no effect on the postprandial intestinal hyperemia but significantly potentiated food-induced increases in oxygen uptake via enhanced oxygen extraction. Furthermore, imidazole had no effect on intestinal glucose absorption. The selective thromboxane synthesis inhibitor U-63557A (5 mg/kg iv) also enhanced oxygen uptake during nutrient absorption and had no effect on the hyperemia or glucose absorption. Our study indicates that inhibition of thromboxane synthesis has no effect on either resting intestinal blood flow or postprandial intestinal hyperemia but significantly enhances postprandial oxygen extraction and uptake. The potentiation of the food-induced increases in oxygen uptake by imidazole and U-63557A appears not to be related to glucose absorption. Endogenous thromboxane therefore appears to inhibit oxygen uptake more than blood flow, and yet does not affect glucose absorption during nutrient absorption.

Topics: Animals; Benzofurans; Blood Pressure; Dogs; Female; Food; Glucose; Hyperemia; Imidazoles; Injections, Intra-Arterial; Intestinal Absorption; Intestines; Jejunum; Male; Oxygen Consumption; Regional Blood Flow; Thromboxane-A Synthase