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A series of new 1,2,3-triazol derivatives, obtained by reaction of 8-azidotetrazol[1,5-a][1,8]naphthyridine with alkynes, is described. Some of the tested compounds showed activity against hypoxia in mice.
The ground state electronic structure of the mixed-valence systems [Ni(2)(napy)(4)X(2)](BPh(4)) (napy=1,8-naphthyridine; X=Cl, Br, I) was studied with combined experimental (X-ray diffraction, temperature dependence of the magnetic susceptibility, and high-field EPR spectroscopy) and theoretical (DFT) methods. The zero-field splitting (zfs) ground S=3/2 spin state is axial with /D/ approximately 3 cm(-1). The iodide derivative was found to be isostructural with the previously reported bromide complex, but not isomorphous. The compound crystallizes in the monoclinic system, space group P2(1)/n, with a=17.240(5), b=26.200(5), c=11.340(5) A, beta=101.320(5) degrees. DFT calculations were performed on the S=3/2 state to characterize the ground state potential energy surface as a function of the nuclear displacements. The molecules can thus be classified as Class III mixed-valence compounds with a computed delocalization parameter, B=3716, 3583, and 3261 cm(-1) for the Cl, Br, and I derivatives, respectively.
A high-performance liquid chromatographic method for the analysis of 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3,7-dicarboxylic acid (I) in plasma and urine is described. A statistical evaluation of the assay technique has shown acceptable accuracy and precision at concentrations as high as 2.0 microgram/ml of plasma or 29.0 microgram/ml of urine for samples augmented with 1. As little as 0.08 microgram/ml of I in plasma or 0.42 microgram/ml of I in urine were quantitatively determined. The mean relative error for the assay of unknown concentrations of I in plasma and urine was +/- 8% and +/- 3%, respectively. This method was used for the analysis of I in the plasma and urine of rhesus monkeys following oral administration of 200 mg/kg of nalidixic acid.
The synthesis of dicopper(I) complexes [Cu2(BBAN)(MeCN)2](OTf)2 (1), [Cu2(BBAN)(py)2](OTf)2 (2), [Cu2(BBAN)(1-Me-BzIm)2](OTf)2 (3), [Cu2(BBAN)(1-Me-Im)2](OTf)2 (4), and [Cu2(BBAN)(mu-O2CCPh3)](OTf) (5), where BBAN = 2,7-bis((dibenzylamino)methyl)-1,8-naphthyridine, py = pyridine, 1-Me-Im = 1-methylimidazole, and 1-Me-BzIm = 1-methylbenzimidazole, are described. Short copper-copper distances ranging from 2.6151(6) to 2.7325(5) A were observed in the solid-state structures of these complexes depending on the terminal ligands used. The cyclic voltammogram of compound 5 dissolved in THF exhibited a reversible redox wave at E1/2 = -25 mV vs Cp2Fe+/Cp2Fe. When complex 5 was treated with 1 equiv of silver(I) triflate, a mixed-valence dicopper(I,II) complex [Cu2(BBAN)(mu-O2CCPh3)(OTf)](OTf) (6) was prepared. A short copper-copper distance of 2.4493(14) A observed from the solid-state structure indicates the presence of a copper-copper interaction. Variable-temperature EPR studies showed that complex 6 has a fully delocalized electronic structure in frozen 2-methyltetrahydrofuran solution down to liquid helium temperature. The presence of anionic ligands seems to be an important factor to stabilize the mixed-valence dicopper(I,II) state. Compounds 1-4 with neutral nitrogen-donor terminal ligands cannot be oxidized to the mixed-valence analogues either chemically or electrochemically.
A homologous series of dinuclear compounds with the bridging ligand 2-(2-pyridyl)-1,8-naphthyridine (pynp) has been prepared and characterized by X-ray crystallographic and spectroscopic methods. [Mo(2)(O(2)CCH(3))(2)(pynp)(2)][BF(4)](2) x 3CH(3)CN (1) crystallizes in the monoclinic space group P2(1)/c with a = 15.134(5) A, b = 14.301(6) A, c = 19.990(6) A, beta = 108.06(2) degrees, V = 4113(3) A(3), and Z = 4. [Ru(2)(O(2)CCH(3))(2)(pynp)(2)][PF(6)](2) x 2CH(3)OH (2) crystallizes in the monoclinic space group C2/c with a = 14.2228(7) A, b = 20.3204(9) A, c = 14.1022(7) A, beta = 95.144(1) degrees, V = 4059.3(3) A(3), and Z = 4. [Rh(2)(O(2)CCH(3))(2)(pynp)(2)][BF(4)](2) x C(7)H(8) (3) crystallizes in the monoclinic space group C2/c with a = 13.409(2) A, b = 21.670(3) A, c = 13.726(2) A, beta = 94.865(2) degrees, V = 3973.9(8) A(3), and Z = 4. A minor product, [Rh(2)(O(2)CCH(3))(2)(pynp)(2)(CH(3)CN)(2)][BF(4)][PF(6)] x 2CH(3)CN (4), was isolated from the mother liquor after crystals of 3 had been harvested; this compound crystallizes in the triclinic space group, P1 with a = 12.535(3) A, b = 13.116(3) A, c = 13.785(3) A, alpha = 82.52(3) degrees, beta = 77.70(3) degrees, gamma = 85.76(3) degrees, V = 2193.0(8) A(3), and Z = 2. Compounds 1-3 constitute a convenient series for probing the influence of the electronic configuration on the extent of mixing of the M-M orbitals with the pi system of the pynp ligand. Single point energy calculations performed on 1-3 at the B3LYP level of theory lend insight into the bonding in these compounds and allow for correlations to be made with electronic spectral data. Although purely qualitative in nature, the values for normalized change in orbital energies (NCOE) of the frontier orbitals before and after reduction are in agreement with the observed differences in reduction potentials as determined by cyclic voltammetry.
In acetonitrile the rigid diphosphine ligand 2,9-bis(diphenylphosphino)-1,8-naphthyridine (dppn) reacts with (SMe2)AuCl in the presence of NaPF6 to produce a pale-yellow material identified as [Au2Na(mu-dppn)3](PF6)3 (1). In acetonitrile dppn reacts with 2 equiv of (SMe2)AuCl to form the simple Au-Cl adduct of the ligand, Au2Cl2dppn (2). In a fashion analogous to that of the synthesis of 1, the reaction of equimolar AgNO3 with dppn produces the trimetallic species [Ag2(mu-dppn)3Ag](PF6)3 (3) as a bright-yellow material. 1, 2, and 3 were characterized by 31P(1H) NMR spectroscopy, electronic absorption spectroscopy, X-ray crystallography, emission spectroscopy, and elemental analysis. Additionally 1 was further characterized by cyclic voltammetry and mass spectrometry. 1.4.5CH3CN.0.5(C2H5)2O (C107H72Au2F18N10.5NaO) crystallizes in the triclinic space group P1 with a = 15.408(3) A, b = 17.295(3) A, c = 22.425(5) A, alpha = 73.68(1) degrees, beta = 77.32(1) degrees, gamma = 74.18(1) degrees, V = 5451.4(19) A3, and Z = 2. C32H24Au2Cl2N2P2 (2) crystallizes in the monoclinic space group Cc with a = 10.936(2) A, b = 19.860(5) A, c = 20.864(2) A, beta = 118.182(1) degrees, V = 3127.3(8) A3, and Z = 4. Compound 3 crystallizes as the bis-DMSO adduct (C101H84Cl2F18N6O2P9S2) in the monoclinic space group C2/c with a = 28.825(7) A, b = 17.013(3) A, c = 23.916(7) A, beta = 115.23(1) degrees, V = 10609.6(44) A3, and Z = 4. The structures of 1 and 3 contain a three-coordinate metal capping the metallocryptate with an encapsulated ion. The central Ag(I) ion in 3 is positioned off-center to form a short Ag...Ag interaction of 3.145(2) A, while the central Na+ ion of 1 is centrally positioned with long Au...Na interactions of approximately 3.5 A. The solution-state properties of 1 were probed. 1 is emissive, as are the Li, K, and Cs analogues.
A palladium-mediated multicomponent domino reaction leading to 2-aryl-4-amino-quinolines and 2-aryl-4-amino[1,8]naphthyridines is reported. The scope of the reaction was examined using carbon monoxide, two 2-ethynyl-arylamines, four aryl iodides, and 10 primary amines as substrates. The selection of the appropriate catalytic system was achieved testing several palladium/phosphine systems and overrides previously reported drawbacks associated with the use of primary amines in related reactions. Moreover several features concerning the role of both palladium [(0) and (II)] and phosphines are reported.
Annelated 2-amino pyridines such as pyrrolo[2,3-b]pyridines, [1,8]naphthyridines, and pyrido[2,3-b]azepines can be synthesized in moderate to good yields in a consecutive one-pot three-component process by a coupling-isomerization-enamine-addition-cyclocondensation sequence of an electron-poor (hetero)aryl halide, a terminal propargyl N-tosylamine, and an N,S-ketene acetal. After the coupling-isomerization sequence, a Diels-Alder reaction with inverse electron demand of the intermediate enimine and the N,S-ketene acetal and subsequent aromatization furnish annelated 2-amino pyridines 4 that were unambiguously characterized by numerous X-ray structure analyses. These heterocycles are highly fluorescent and partially pH sensitive, and their electronic structure was studied with spectroscopic and computational methods.
A series of di-Mannich bases derived from 4-[7'-bromo (and chloro)-1',5'-naphthyridin-4'-ylamino]phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol were assayed for activity against chloroquine-sensitive and chloroquine-resistant isolates of cultured Plasmodium falciparum using the inhibition of uptake of radiolabelled hypoxanthine. A number of the 4-(7'-trifluoromethylquinolinyl-amino)phenols showed statistically superior activity to chloroquine and amodiaquine against both isolates. Analysis of the antimalarial activity of some of these compounds against Plasmodium berghei in mice following oral administration again demonstrated activity equal or superior to that of the established antimalarials against a chloroquine-sensitive strain, and in some cases appreciably superior activity against a chloroquine-resistant strain.
The title complex, [Ag4(C7H5O3)2(C8H6N2)4(C7H6O3)4], lies about an inversion centre and has a unique tetranuclear structure consisting of four Ag(I) atoms bridged by four N atoms from two 1,8-naphthyridine (napy) ligands to form an N:N'-bridge and four O atoms from two salicylate (SA) ligands to form an O:O'-bridge. The Ag atoms have distorted octahedral coordination geometry. The centrosymmetric Ag4 ring has Ag-Ag separations of 2.772 (2) and 3.127 (2) A, and Ag-Ag-Ag angles of 107.70 (4) and 72.30 (4) degrees . All SA hydroxy groups take part in intramolecular O-H...O hydrogen bonding. In the crystal packing, the napy rings are oriented parallel and overlap one another. These pi-pi interactions, together with weak intermolecular C-H...O contacts, stabilize the crystal structure.
Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H2O2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 microM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid beta25-35-induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca2+ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2. In conclusion, ITH4012 is a tacrine derivative that maintains acetylcholinesterase-inhibiting activity (IC50=0.8 microM) but has the additional property of acting as a calcium promotor, a property leading to neuroprotection through the induction of antiapoptotic proteins.
4-Oxo-1,8-naphthyridine- and 4-oxoquinoline-3-carboxylic acids (2a, b and 3a-1) possessing a 1-amino-cyclopropyl group at the 7-position have been synthesized and evaluated for in vitro antibacterial activities. The three quinolones (3d, h, i) exhibited potent antibacterial activities against both gram-positive and gram-negative bacteria, which are comparable to those of ciprofloxacin (CPFX) and ofloxacin (OFLX). Among the three compounds, the best pharmacological and pharmacokinetic profile was obtained with 3i, an OFLX analogue, which was considerably less toxic than three reference quinolones (1, CPFX and OFLX).
Effect of (+/-)-methyl 3-ethyl-2,3,3a,4-tetrahydro-1H-indolo[3,2,1-de] [1,5] naphthyridine-6-carboxylate hydrochloride (OM-853), a new vincamine analogue, on the metabolism and function of cerebral 5-hydroxytryptamine (5-HT) neurons was investigated using male Wistar rats. The single administration of OM-853 (200 mg/kg, p.o.) induced the facilitation of metabolic turnover of 5-HT in various brain areas except the cerebral cortex, pons-medulla and cerebellum. In vitro addition of OM-853 inhibited the uptake of [14C]5-HT in striatal slices only at a high concentration (10(-4) M). On the other hand, a low concentration of OM-853 (10(-8)-10(-6) M) induced the increase of the spontaneous and high K+ (30 mM)-evoked releases of [14C]5-HT from striatal slices. OM-853 had more potent inhibitory effect on the binding of [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-hydroxy DPAT) to 5-HT1A receptors and/or 5-HT autoreceptors than that of [3H]-ketanserin to 5-HT2 receptors. The stimulatory effect of OM-853 (10(-7) M) on [14C]5-HT release was antagonized by 10(-7) M 8-hydroxy DPAT, which is known to act at presynaptic 5-HT autoreceptors as an agonist. These results suggest that OM-853 may induce facilitation of 5-HT turnover by enhancing 5-HT release, probably via the inhibition of presynaptic 5-HT autoreceptor.
A new fluorescent functional monomer DMAAN has been designed and synthesized for the first time. The monomer was expected to bind with cytosine via complementary hydrogen bonding under certain experimental conditions. The synthetic procedure of DMAAN is as follows. A suspension of 2,6-diaminopyridine in phosphoric acid was added to acetylacetone. The mixture was warmed for thirty minutes on a steam-bath. Then 2,4-dimethyl-7-amino-1,8-naphthyridine(DMAN, mp 216-218 degrees C) was obtained. DMAAN was prepared by the reaction of DMAN with acryloyl chloride in chloroform and triethylether mixed solvent. Acryloyl chloride in anhydrous chloroform was added dropwise over 30 minutes with constant stirring at 4 degrees C. The melting point of the final product was 239-241 degrees C. Mass spectrometry and proton NMR were used to confirm the chemical structure of DMAN and DMAAN. The products were also characterized by UV and fluorescence spectrometry.
The inhibitory effect of fumaric acid (FA) on carcinogenesis by potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (trans, NFN) was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFN-induced stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1 early-stage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early-stage adenocarcinomas were noted in 7 and 11 animals, respectively.
The stimulation of the formation of inositol phosphate (IP) by (+-)-methyl-2,3,3a,4-tetrahydro-1H-indolo [3,2,1-de] [1,5] naphthyridine-6-carboxylate monohydrochloride (vinconate), a novel indolonaphthyridine derivative, was studied using both cerebral cortical slices and crude synaptic membranes prepared from the rat brain. Vinconate (10 mM-1 mM) inhibited the binding of [3H]quinuclidinyl benzilate to the muscarinic receptor in a dose-dependent manner and the IC50 value for [3H]quinuclidinyl benzilate binding was found to be 17 microM. The rightward shift of the inhibition curve of [3H]quinuclidinyl benzilate binding by carbachol in the presence of GTP (100 microM) was abolished by vinconate (100 microM). Carbachol (10 nM-10 mM) significantly increased [3H]IP formation in a dose-dependent manner and the rate of [3H]IP formation mediated by carbachol stimulation was significantly accentuated in the presence of 10 microM vinconate. The enhancement of [3H]IP accumulation by vinconate was inhibited by approximately 50% in the presence of atropine (1-1000 microM), although up to 1 mM of phentolamine and ketanserin had no effect on the vinconate-induced increase of phosphatidylinositol turnover. Moreover, vinconate significantly accentuated 20 mM KCl-evoked stimulation of [3H]IP formation. Vinconate had no differential effect on the ratio of IP or inositol 1,4-biphosphate and inositol 1,4,5-triphosphate formations. These results suggest that vinconate may induce a facilitation of phosphatidylinositol turnover via the stimulation of muscarinic receptors and a facilitation of coupling between muscarinic receptors and GTP-binding protein. The presence of a direct stimulatory effect of vinconate on phosphatidylinositol turnover has also been suggested.
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