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PubMed2006

N, N' (4,5-dihydro-1h-imidazol-2-yl)3-aza-1,10-decane-diamine and N, N'(4,5-dihydro-1H-imidazol-2-yl)3-aza-1, 10-dodecane-diamine antagonize cell proliferation as selective ligands towards topoisomerase II.

New alkyl imidazoline derivatives have been synthesized as potential anti-cancer agents. The anti-proliferative activity of these compounds, evaluated against representative human haematological and solid neoplastic cell lines, showed that N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-decane-diamine (8) and N, N'-di (4,5-dihydro-1H-imidazol-2-yl)3-aza-1,10-dodecane-diamine (9) were the most active compounds; in fact, they inhibited the cell proliferation at submicromolar concentrations. In enzyme assays, compound 9 turned out to be an inhibitor of topoisomerase II at concentrations comparable with those of the reference topoisomerase II inhibitor, etoposide.

Alkanes↗
PubMed1987

Effects of imidazole and some imidazole-derivatives on lisuride-induced mounting and aggressiveness.

Adult male rats were treated intraperitoneally (IP) with imidazole (IMID), distilled water or saline prior to administration of lisuride either IP or intracerebroventricularly (ICV) at doses too low by themselves to elicit the behavioural signs of mounting and aggressiveness, typically induced by higher doses of this drug. Pretreatment with distilled water or saline, or the procedure of injection alone, stimulated mounting in some of the animals. At a certain range of doses IMID induced a marked increase in both mounting and aggressive posturing in the same animals, while at higher doses mounting ceased, violent aggressive behaviour appeared and some of the rats died. Seven IMID derivatives were used on the lisuride-test: N-methylimidazole, 2-methylimidazole, 4-methylimidazole, N-acetylimidazole, 4-imidaaoleacetic acid, clonidine and cimetidine. Only 4-imidazoleacetic acid was completely ineffective with respect to controls. All the other drugs enhanced aggressive behaviour to varying degrees but proved to be less potent than IMID in inducing mounting, and clonidine reduced mounting at all the doses tested.

Aggression↗
PubMed1991

Direct prediction of dissociation constants (pKa's) of clonidine-like imidazolines, 2-substituted imidazoles, and 1-methyl-2-substituted-imidazoles from 3D structures using a comparative molecular field analysis (CoMFA) approach.

The applicability of a comparative molecular field analysis (CoMFA) method to reproduce and predict the pKa values of 28 clonidine-like imidazoline analogues and 16 2-substituted imidazoles has been investigated with the GRID force field. Molecular fields calculated with an H+ probe and AM1 partial atomic charges produced a correlation with a small standard deviation and a high correlation coefficient with cross validation. It was concluded that the CoMFA treatment of electrostatic effects is suitable for predicting pKa values and thus for the examination of the electronic effects in 3D quantitative structure-activity relationships.

Clonidine↗
PubMed1978

Antimycotic imidazoles. 2. Synthesis and antifungal properties of esters of 1-[2-hydroxy(mercapto)-2-phenylethyl]-1H-imidazoles.

The synthesis of carboxylic and (thio)carbonate esters of 1-[2-hydroxy(mercapto)-2-phenylethyl]-1-H-imidazoles, some of which are formally related to miconazole and its analogues by replacement of an ether with an ester linkage, is described. In antifungal bioassays a number of compounds display in vitro and, in a few cases, in vivo activities comparable to that of miconazole. In this series lipophilicity within a relatively narrow range is shown to be a necessary, although not sufficient, criterion for in vitro and, in particular, in vivo antifungal activity.

Animals↗
PubMed2004

Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist.

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.

Adrenergic alpha-1 Receptor Agonists↗
PubMed2005

Synthesis of trisubstituted imidazoles by palladium-catalyzed cyclization of O-pentafluorobenzoylamidoximes: application to amino acid mimetics with a C-terminal imidazole.

1-Benzyl-4-methylimidazoles with a range of substituents at the 2-position are prepared from O-pentafluorobenzoylamidoximes on treatment with catalytic amounts of Pd(PPh3)4 and triethylamine. The sequence provides access to optically active amino acid mimetics with a C-terminal imidazole. [structure: see text]

Amino Acids↗
PubMed1999

Imidazole-imidazole pair as a minor groove recognition motif for T:G mismatched base pairs.

The T:G mismatched base pair is associated with many genetic mutations. Understanding its biological consequences may be aided by studying the structural perturbation of DNA caused by a T:G base pair and by specific probing of the mismatch using small molecular ligands. We have shown previously that AR-1-144, a tri-imidazole (Im-Im-Im) minor groove binder, recognizes the sequence CCGG. NMR structural analysis of the symmetric 2:1 complex of AR-1-144 and GAACCGGTTC revealed that each AR-1-144 binds to four base pairs with the guanine N2 amino group forming a bifurcated hydrogen bond to a side-by-side Im/Im pair. We predicted that the free G-N2 amino group in a T:G wobble base pair can form two individual hydrogen bonds to a side-by-side Im/Im pair. Thus an Im/Im pair may be a good recognition motif for a T:G base pair in DNA. Cooperative and tight binding of an AR-1-144 homodimer to GAACTGGTTC permits a detailed structural analysis by 2D NOE NMR refinement and the refined structure confirms our prediction. Surprisingly, AR-1-144 does not bind to GAATCGGTTC. We further show that both the Im-Im-Im/Im-Py-Im heterodimer and the Im-Im-Im/Im-Im-Im homodimer bind strongly to the CACGGGTC + GACTCGTG duplex. These results together suggest that an Im/Im pair can specifically recognize a single T:G mismatch. Our results may be useful in future design of molecules (e.g. linked dimers) that can recognize a single T:G mismatch with specificity.

Base Pair Mismatch↗
PubMed1986

Bicyclic compounds with potential antiulcer and/or antisecretory activity. II. 1(or 3),4,6,7-Tetrahydro-1(3)H-pyrano[3,4-d]imidazoles and 1(or 3),4,6,7-tetrahydro-1(3)H-thiopyrano[3,4-d]imidazoles.

Owing to our current interest in synthesizing and evaluating the antiulcer and antisecretory activity of bicyclic compounds, a series of 1(or 3),4,6,7-tetrahydropyrano- and 1(or 3),4,6,7-tetrahydrothiopyrano-[3,4-d]imidazoles was synthesized and tested. The biological results were compared with those of some previously described 4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine and 4,5,6,7-tetrahydrobenzimidazole derivatives.

Animals↗
PubMed1982

New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase.

The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.

Adenine Phosphoribosyltransferase↗
PubMed2005

Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists.

In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4-n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs the thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g) showed pA2 = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.

Animals↗
PubMed2004

Supramolecular spin-crossover iron complexes based on imidazole-imidazolate hydrogen bonds.

The [Fe(II)(H(3)L)](BF(4))(2).3H(2)O (1) complex was synthesized, where H(3)L (tris[[2-[(imidazole-4-yl)methylidene]amino]ethyl]amine) is a tripodal ligand obtained by condensation of tris(2-aminoethyl)amine and 4-formylimidazole (fim) in a 1:3 molar ratio. Starting from 1, a series of complexes, [Fe(II)(H(1.5)L)](BF(4))(0.5) (2) (=[Fe(II)(H(3)L)][Fe(II)(L)]BF(4)), [Fe(H(1.5)L)]BF(4) (3) (=[Fe(II)(H(3)L)][Fe(III)(L)](BF(4))(2)), [Fe(III)(H(3)L)](BF(4))(3).fim.H(2)O (4), and [Fe(III)(L)].2.5H(2)O (5), has been synthesized and characterized. The single-crystal X-ray structure of each complex has been determined. The Fe(II) compound, 2, and a mixed valence Fe(II)-Fe(III) compound, 3, involve formally hemi-deprotonated ligands, H(1.5)L. The structure of 3 consists of a homochiral two-dimensional assembled sheet, arising from the intermolecular hydrogen bonds between [Fe(II)(H(3)L)](2+) and [Fe(III)(L)](0) (3). All but 5 exhibit spin crossover between low-spin (LS) and high-spin (HS) states. This is a rare case where both Fe(II) and Fe(III) complexes containing the same ligand exhibit spin-crossover behavior. Magnetic susceptibility and Mössbauer studies showed that 3 has three accessible electronic states: LS Fe(II)-LS Fe(III), HS Fe(II)-LS Fe(III), and HS Fe(II)-HS Fe(III). Compounds 1-3 show the light-induced excited spin-state trapping effect at the Fe(II) sites upon irradiation with green light. The solution magnetic properties, electronic spectra, and electrochemical properties of 1, 4, and 5 were also studied.

Journal Article↗
PubMed1993

Nonpeptide angiotensin II receptor antagonists. 2. Design, synthesis, and structure-activity relationships of 2-alkyl-4-(1H-pyrrol-1-yl)-1H-imidazole derivatives: profile of 2-propyl-1-[[2'-(1H-tetrazol-5-yl)-[1,1' -biphenyl]-4-yl]-methyl]-4-[2-(trifluoroacetyl)-1H-pyrrol-1-yl]-1H- imidazole-5-carboxylic acid (CI-996).

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

Angiotensin Receptor Antagonists↗
PubMed1999

Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)-cyclopropylamine.

Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD2 = 7.1; alpha = 0.75) and on guinea pig jejunum (pD2 = 6.6; alpha = 0.75). Its enantiomer, (1R, 2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H3 receptor ligands.

Animals↗
PubMed2001

1:2 Complexes of chloranilic acid with pyrazole and imidazole, and the acetonitrile solvate of a 1:1 complex with imidazole.

2,5-Dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid) forms X-H.Y (X, Y = N or O) and C-H.Cl hydrogen bonds with pyrazole and imidazole to afford bis(pyrazolium) dichloroanilate and bis(imidazolium) dichloroanilate, (I) and (II), both 2C(3)H(5)N(2)(+).C(6)Cl(2)O(4)(2-), and imidazolium chloroanilate acetonitrile solvate, C(3)H(5)N(2)(+).C(6)HCl(2)O(4)(-).C(2)H(3)N, (III). Their crystal structures demonstrate three novel supramolecular architectures based on supramolecular synthons to build a ladder, (I), a two-dimensional network, (II), and a flat ribbon, (III).

Journal Article↗
PubMed2004

Bis[tris(1-methyl-1H-imidazol-2-yl)phosphine-kappa3N3]iron(II) tetrachloroferrate(II) methanol tetrasolvate (ca 153 K) and bis[tris(1-methyl-1H-imidazol-2-yl)methanol-kappa3N3]iron(III) bis[tetrachloroferrate(III)] chloride (redetermination, ca 153 K).

The first of the title compounds, [Fe(C12H15N6P)2][FeCl4].4CH4O, is the first homoleptic bis(ligand)iron(II) species reported for this phosphorus bridgehead ligand; interestingly, the complex is isomorphous with its tris(1-methyl-1H-imidazol-2-yl)methanol counterpart, the second of the title compounds, [Fe(C13H16N6O)2][FeCl4]2Cl. In both compounds, the Fe atom of the cation lies on an inversion centre. The structure determinations presented here allow an interesting comparison of iron(II) and iron(III) species in similar coordination environments.

Journal Article↗
PubMed2005

catena-Poly[[[mu-1,4-bis(imidazol-1-ylmethyl)benzene-kappa2N3:N3']bis[dichlorocopper(II)]]-bis[mu-1,4-bis(imidazol-1-ylmethyl)benzene]-1:1'kappa2N3:N3';2:2'kappa2N3:N3'].

The title compound, [Cu2Cl4(bix)3]n [bix is 1,4-bis(imidazol-1-ylmethyl)benzene, C14H14N4], has been synthesized by the hydrothermal method. The copper(II) center has a five-coordinate trigonal-bipyramidal geometry. Each bix ligand binds with two CuII ions, forming ladder-like structures which are connected by pi-pi stacking interactions to form a two-dimensional network.

Journal Article↗
PubMed2001

Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of vulvovaginal candidiasis (thrush). OBJECTIVES: The primary objective of this review was to assess the relative effectiveness of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. The secondary objectives of the review were to assess the cost-effectiveness, safety and patient preference of oral versus intra-vaginal anti-fungals. SEARCH STRATEGY: The following sources were searched: The Cochrane Library (Issue 4, 1999), MEDLINE (January 1985 to May 2000), EMBASE (January 1980 to January 2000) and the Cochrane Collaboration Sexually Transmitted Disease Group Specialised Register of Controlled Trials. The reference lists of retrieved articles were reviewed manually. The manufacturers of anti-fungals available in the UK were contacted. SELECTION CRITERIA: ~Bullet~Randomised controlled trials published in any language. ~Bullet~Trials had to compare at least one oral anti-fungal with one intra-vaginal anti-fungal. ~Bullet~Women (aged 16 years or over) with uncomplicated vulvovaginal candidiasis. ~Bullet~The diagnosis of vulvovaginal candidiasis to be made mycologically (i.e. a positive culture and / or microscopy for yeast). ~Bullet~Trials were excluded if they solely involved subjects who were HIV positive, immunocompromised, pregnant, breastfeeding or diabetic. ~Bullet~The primary outcome measure was clinical cure. DATA COLLECTION AND ANALYSIS: Duplicate scrutiny was performed of the titles and abstracts of the electronic search results. Full article formats of all selected abstracts were retrieved and independently assessed by two reviewers. Independent duplicate abstraction was performed by four reviewers. Disagreements regarding trial inclusion or data abstraction were resolved by discussion between the reviewers. Odds ratios were pooled using the random effects model. Chi-squared tests with a p-value of less than 0.1 indicated heterogeneity in the results. MAIN RESULTS: Seventeen trials are included in the review, reporting 19 oral versus intra-vaginal anti-fungal comparisons. No statistically significant differences were shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short term (OR 1.00 (95% CI, 0.72 to 1.40)) and long term (OR 1.03 (95% CI, 0.72 to 1.49)) follow-up. No statistically significant differences for mycological cure were observed between oral and intra-vaginal treatment at short term (OR 1.20(95% CI, 0.87 to 1.65)) or long term follow-up (OR 1.30 (95% CI, 0.99 to 1.71)). Two trials each reported one withdrawal from treatment due to an adverse reaction. Treatment preference data were poorly reported. REVIEWER'S CONCLUSIONS: No differences exist in terms of the relative effectiveness (measured as clinical and mycological cure) of anti-fungals administered by the oral and intra-vaginal routes for the treatment of uncomplicated vaginal candidiasis. No definitive conclusion can be made regarding the relative safety of oral and intra-vaginal anti-fungals for uncomplicated vaginal candidiasis. The oral route of administration is the preferred route for anti-fungals for the treatment of vulvovaginal candidiasis. The decision to prescribe or recommend the purchase of an anti-fungal for oral or intra-vaginal administration should take into consideration: safety, cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications: if women are purchasing their own treatment, they should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of oral anti-fungal administration is worth the gain in convenience, if this is the patient's preference.

Administration, Intravaginal↗