Imidazolyl Ring Research Articles

Synthesis and biological assays of new H 3-antagonists with imidazole and imidazoline polar groups

New histamine H 3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [ 3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives ( 2a– f) with tetramethylene chain (p K i 8.03–8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles ( 1a– i) and that of 2-alkylthioimidazolines ( 3a– h). In contrast, a general lowering of affinity (p K i 5.90–7.63) was observed for compounds of the last series ( 3a– h), with a complex dependence on the terminal lipophilic group and chain length.

N—H...N Hydrogen Bonding in the Four Independent Molecules of (2S,4S,5R)-(−)-2-(1H-Imidazol-2-yl)-3,4-dimethyl-5-phenyl-1,3-oxazolidine, with C-H...πarene, C-H...O and C-H...πC=CInteractions

The title compound, C 14 H 17 N 3 O, prepared from (1R,2S)-(-)-ephedrine, crystallizes in space group P2 1 with four molecules in the asymmetric unit. The molecules, in pairs, take part in intermolecular N-H...N hydrogen bonding between the imidazolyl rings, forming one-dimensional chains with alternating N...N distances of 2.866 (3)/2.883(3) and 2.945 (3)/2.956(3) A. Inter-chain C arene -H...π arene, C arene -H...C and C sp 3-H...πC=C interactions generate a three-dimensional network.

Synthesis and characterization of a partially quaternized poly(1-vinylimidazole) bound to a ruthenium(II) complex and a viologen moiety

Three metallopolymers having both a photosensitizer and an electron acceptor on the same polymer backbone were prepared and characterized by UV-Vis absorption and fluorescence spectroscopies and thermal measurements as differential scanning calorimetry (DSC) and thermogravimetric differential analysis (TG/DTA). These metallopolymers consist of bis(2,2′-bipyridine)ruthenium(II) complexes as a photosensitizer and a viologen species as an electron acceptor linked covalently to the imidazolyl residues on partially quaternized poly(1-vinylimidazole) through an alkyl spacer. DSC curves showed a glass transition temperature at ca. 230°C and an exothermic peak around 170°C. The exothermic peak was assigned to the cleavage of the alkyl spacer between the viologen and the quaternized imidazolium segment. UV-vis absorption spectra showed that these polymers have three absorption maxima, the metal-to-ligand charge transfer band (MLCT) of the ruthenium(II) complex residue being in the visible region and two electronic transition bands deriving from the viologen residue and the imidazolyl ring in the UV region. These absorption maxima are independent of the length of the alkyl group in the viologen residues and the spacer between the imidazolyl and the viologen segment. However, the luminescence spectra depend significantly on the length of alkyl group and the spacer, demonstrating that part of the ruthenium(II) complex residues are quenched by viologen residues. Furthermore, quenching studies revealed that these polymers contain at least four ruthenium(II) complex residues on the same polymer backbone.

Synthesis and characterization of a partially quaternized poly(1-vinylimidazole) bound to a ruthenium(II) complex and a viologen moiety

Three metallopolymers having both a photosensitizer and an electron acceptor on the same polymer backbone were prepared and characterized by UV-Vis absorption and fluorescence spectroscopies and thermal measurements as differential scanning calorimetry (DSC) and thermogravimetric differential analysis (TG/DTA). These metallopolymers consist of bis(2,2′-bipyridine)ruthenium(II) complexes as a photosensitizer and a viologen species as an electron acceptor linked covalently to the imidazolyl residues on partially quaternized poly(1-vinylimidazole) through an alkyl spacer. DSC curves showed a glass transition temperature at ca. 230°C and an exothermic peak around 170°C. The exothermic peak was assigned to the cleavage of the alkyl spacer between the viologen and the quaternized imidazolium segment. UV-vis absorption spectra showed that these polymers have three absorption maxima, the metal-to-ligand charge transfer band (MLCT) of the ruthenium(II) complex residue being in the visible region and two electronic transition bands deriving from the viologen residue and the imidazolyl ring in the UV region. These absorption maxima are independent of the length of the alkyl group in the viologen residues and the spacer between the imidazolyl and the viologen segment. However, the luminescence spectra depend significantly on the length of alkyl group and the spacer, demonstrating that part of the ruthenium(II) complex residues are quenched by viologen residues. Furthermore, quenching studies revealed that these polymers contain at least four ruthenium(II) complex residues on the same polymer backbone.

Synthesis and characterization of a partially quaternized poly(1-vinylimidazole) bound to a ruthenium(II) complex and a viologen moiety

Three metallopolymers having both a photosensitizer and an electron acceptor on the same polymer backbone were prepared and characterized by UV-Vis absorption and fluorescence spectroscopies and thermal measurements as differential scanning calorimetry (DSC) and thermogravimetric differential analysis (TG/DTA). These metallopolymers consist of bis(2,2′-bipyridine)ruthenium(II) complexes as a photosensitizer and a viologen species as an electron acceptor linked covalently to the imidazolyl residues on partially quaternized poly(1-vinylimidazole) through an alkyl spacer. DSC curves showed a glass transition temperature at ca. 230°C and an exothermic peak around 170°C. The exothermic peak was assigned to the cleavage of the alkyl spacer between the viologen and the quaternized imidazolium segment. UV-vis absorption spectra showed that these polymers have three absorption maxima, the metal-to-ligand charge transfer band (MLCT) of the ruthenium(II) complex residue being in the visible region and two electronic transition bands deriving from the viologen residue and the imidazolyl ring in the UV region. These absorption maxima are independent of the length of the alkyl group in the viologen residues and the spacer between the imidazolyl and the viologen segment. However, the luminescence spectra depend significantly on the length of alkyl group and the spacer, demonstrating that part of the ruthenium(II) complex residues are quenched by viologen residues. Furthermore, quenching studies revealed that these polymers contain at least four ruthenium(II) complex residues on the same polymer backbone.

17-Imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives. Novel steroidal inhibitors of human cytochrome C17,20-lyase (P450(17 alpha).

We recently described a number of inhibitors of P450(17 alpha), the key enzyme of androgen biosynthesis. Here, we report the synthesis and activity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivatives were prepared by condensing the corresponding 17-ketol acetate side chain with aldehyde and ammonium hydroxide. The 17 beta-(4'imidazolyl) derivatives (2a, 2e, 4a, 4c) were found to be potent inhibitors of human testicular P450(17 alpha), with greater activity than ketoconazole. The juxtaposition between the imidazole ring and the steroid D ring appears to be important in contributing inhibitory properties, Compounds having a 17 beta-(2'-imidazolyl) ring (9a, 10) or a 20 beta-(2'-imidazolyl) ring (12), instead of the 17 beta-(4'-imidazolyl) ring (2a, 4a), are weak inhibitors. Among the 17-(4'-imidazolyl) derivatives, introduction of the 17 alpha-hydroxy group (4b) and 16 alpha,17 alpha-epoxide group (2d) diminished potency (2a-->2d; lC50 66-->430 nM; 4a-->4b; lC50 58-->1200 nM), while the 16,17 double bond increased the inhibitory activity by almost three times in the 5-en-3 beta-ol inhibitors (2a-->2e; lC50 60-->24 nM). There was virtually no difference in the inhibitory activity in the 4-en-3-one inhibitors (4a-->4c; IC50 58-->50 nM). The introduction of a methyl (2b) or phenyl group (2c) on the 2'-position of 4'-imidazolyl ring caused a dramatic decrease in the potency. As to modification of the A,B rings, the 3-acetate (2f, 2g) decreased the potency almost 3-fold compared with the 3-alcohol (2e-->2f, IC50 24-->75 nM; 2a-->2g, 66-->199 nM) and the conversion from the 5-en-3 beta-ol into the 4-en-3-one hardly affected the potency. As expected, 4c was more potent than 2e for the rat p450(17 alpha). 17-(3'Pyrazolyl)-(14b) and 17-(5'-isoxazolyl)-androsta-5,16-dien-3 beta-ol (15b) were also potent inhibitors of P450(17 alpha), whereas the 17-(2'-imidazolyl) compound (9b) was one of the most potent inhibitor in this series. However, their 16-saturated counterparts (9a, 14a, 15a) were weak inhibitors. The 17 beta-(3'-isoxazolyl)- (16) and 17 beta-(5'-methyl-3'-oxazolyl)androst-5-en-3 beta-ol (18) were also inactive. The introduction of a methyl of phenyl group on the nitrogen of the pyrazolyl ring of 14b [see 14c, 14d, and 14e] also caused some loss of inhibition for P450(17 alpha). Compounds 2e, 4a, 4c, 9b, 14d, 17a, and 17b are among the most potent inhibitors of human P450(17 alpha) so far reported.

Ethyl 3-(5-amino-4-cyano-1-imidazolyl-amino)-2-butenoate: an example of a combined inter- and intramolecular bifurcated hydrogen bond

The imidazolyl ring is twisted out of the 2-butenoate plane (C-N-N-C) by 80.9 (4) o and delocalization occurs along a planar chain region extending from the amine to the carbonyl O atom. This O atom is also linked to the amine via an intramolecular hydrogen bond [O...N 2.747 (4), O...H 2.21 (3) A, N-H...O 121 (3) o ] which may explain why the ester carbonyl stretching vibration in the IR spectrum is shifted to lower frequency (1656 cf. 1730 cm -1 for a similar compound with no intramolecular hydrogen bonding). The same H and O atoms also take part in intermolecular hydrogen bonding around a crystallographic inversion centre [O...N 2.932 (4), O...H 2.19 (3) A, N-H...O 144 (3) o ]

Synthesis of polyorganosiloxanes with imidazolyl groups in the side chain

AbstractAn imidazolyl ring was introduced into the side chain of poly(3‐chlorocarbonylpropylmethyl‐siloxane) (4) by esterification with 4(5)‐hydroxymethylimidazole (1), the imino group being protected during esterification by the 2‐nitrobenzyl group which can be easily cleaved by UV light irradiation without attacking the main chain. The photolytic cleavage of the 2‐nitrobenzyl group was completed with a yield of ≈ 100% after 2 h without any remarkable side reaction. The polyorganosiloxanes (6), with a high content of imidazolyl groups in the side chain, are slightly soluble in hot DMSO and DMF. From this fact, in addition to the result of the measurement of Tg, it is suggested that very strong intermolecular hydrogen bonds are operating.

Coordination chemistry of methylmercury(II). Complexes of aromatic nitrogen donor tripod ligands involving new coordination geometries for methylmercury(II)

Complexes [MeHgL]N03 {L = diphenyl(2-pyridy1)methane (pyCHPh2), bis(2-pyridy1)phenylmethane [(py)2CHPh], and the tripod ligands tris(2-pyridy1)carbinol [(py)3COH] and bis(2-pyridyl)(N-methyl-2-imidazolyl)carbinol [(py)2(NMeIm)COH]} are obtained from addition reactions in acetone. The ligand (py)2CHPh is formed on reaction of (2-benzylpyridy1)lithium with 2-bromopyridine. 1H NMR spectra indicate that (py)2CHPh and (py)2(N-Me1m)COH are present as bidentates in methanol solutions of their complexes, with the latter coordinated via the imidazolyl ring and one pyridyl ring. Spectra are consistent with the presence of weak pi interactions between mercury and phenyl rings in the (py)CHPh2 and (py)2CHPh complexes and the uncoordinated pyridyl ring in the (py)2(N-Me1m)COH complex. In complexes [MeHgL]N03 (L = (py)3OH, (py)3CH) the ligands are present as tridentates in methanol. Crystalline [MeHgL]NO3 [L = (py)3OH, (py)2(N-MeIm)COH] have the tripod ligands coordinating as tridentates, with irregular coordination geometries based on a dominant C-Hg-N’ moiety [Hg-N’ = 2.28 (1) A, C-Hg-N’ = 150(1)O ((py)3COH) and 2.13(1) A, 170(0) ((py)2(N-MeIm)COH)] with weaker Hg-N,N” bonds [2.45(l), 2.53(1) ((py)3OH) and 2.66(l), 2.71(1) A ((py)2(N-MeIm)COH)]. For [MeHg((py)2(N-MeIm)COH)] the coordination geometry resembles a trigonal bipyramid lacking one equatorial donor and with axial direction C-Hg-N’.

Synthesis of potential platinum(II) anti-tumor complexes: Complexes containing bidentate pyridyl and imidazolyl donors

The synthesis of complexes PtCl2(L2) of some bidentate ligands (L2) containing pyridyl rings connected by a carbon atom, di-2-pyridylmethane (py2CH2) and py2SEt2, and containing both pyridyl and imidazolyl rings, (2,2’-pyridyl)imidazole (pyIm) and py-NMeIm. Preliminary screening of the complexes, including the 2,2’-bipyridyl complex and cis-PtL2Cl2 (L = NH3, pyridine), on cultures of L1210 mouse leukemia cells has been carried out. Results were obtained over a range of concentrations required to give lo-90% inhibition of growth, and the expected sigmoidal curves (percent growth vs. concentration) were obtained. The complex cis-Pt(pyridine)2Cl2 gave an I.D.50 value higher than that of cis-Pt(NH3)2C12, consistent with earlier studies showing that this complex has lower activity than cis-Pt(NH3)2Cl2 against Ehrlich ascites and Sarcoma 180 tumors in mice. The complex Pt(pyIm)C12. H20 gave an I.D.50 value similar to that of cis- Pt(NH3)2Cl2, and below values for the other complexes. These results suggest that further testing with tumor bearing animals is warranted for Pt(pyIm)C12. H20.

Biological activity of a new class of rifamycins. Spiro-piperidyl-rifamycins.

The biological properties of spiro-piperidyl-rifamycins, a new class of rifamycin antibiotics, are described. In these derivatives the positions 3 and 4 have been incorporated into an imidazolyl ring bearing a spiro-piperidyl group N substituted with linear and branched aliphatic chains. The in vitro antibacterial activity against Staphylococcus aureus and Mycobacterium tuberculosis increases with the number of the carbon atoms in the linera side chain, whereas the inhibitory effect on Escherichia coli is lowered. The antibacterial activity is only marginally affected by branching of the side chain. In vivo (experimental infections of mice) the optimal therapeutic activity against M. tuberculosis is shown by compounds bearing 3 approximately 5 carbon atoms as a linear or branched side chain; in comparison with rifampicin, the potency of these derivatives is 2 approximately 3 times higher. The finding is in a good agreement with the exceptional tissue tropism, which seems to be a favourable property of this group of derivatives.

A tritium exchange method for characterization of modified histidyl residues and its application to fumarase

A technique using tritium incorporation into the C-2 position of the imidazolyl ring of histidine for the identification of alkylated histidyl residues is reported. The first-order rate constant for the incorporation of tritium from water into N-methylhistidine (pH 8.0, 80°C) is 3.3 × 10 −2 min −1 ( t 1 2 = 21 min ). No other amino acid tested gave more than 0.3% as much incorporation of tritium as did N-methylhistidine. A modified amino acid residue derived from fumarase which had been inactivated by the bifunctional reagent 3,4-bis(bromomethyl) benzoate (I) was conclusively identified as a histidine-I adduct by the above characterization procedure. The technique of measuring tritium incorporation allows the qualitative identification of compounds as histidyl (or imidazolyl) or, alternatively, the quantitative determination of known histidyl compounds, both at picomole levels.

Catalysis of ester hydrolysis by cationic micelles of surfactants containing the imidazole ring

Micelles of cetyl(imidazol-4-ylmethyl)dimethylammonium chloride, (CDAIM)(IIa), are good catalysts for the hydrolysis of p-nitrophenyl esters in the pH range 7.2–9.2. The large pH dependence of the catalytic activity is indicated by the enhanced contribution of the anionic form of the imidazolyl ring at the polar head of the surfactant. The catalytic effects of CDAIM are compared with those of Nα-myristoylhistidine (MirHis)(Ia) in cationic micelles. The two imidazole-containing surfactants differ markedly in several respects such as the micellar activity in neutral solution, the change in catalytic effect with changing pH, and the rate of regeneration of the micellar active site. A cross examination of the effects of CDAIM and MirHis and those of the corresponding non-surfactant analogues (IIb) and (Ib), allows a dissection of the micellar and structural factors responsible for catalytic activity. Much of the difference observed between CDAIM and MirHis is accounted for by structural factors which make the imidazole ring in compounds (II) a much weaker (by ca.3 pK units) base than that of histidine derivatives (I).