Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMIDINES”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2003

Organoruthenium(II) and (III) amidinates, (eta5-C5Me5)Ru(eta-amidinate) and (eta5-C5Me5)RuCl(eta-amidinate), as unique redox catalysts for the intramolecular Kharasch reactions: facile access to a pyrrolizidine alkaloid skeleton under mild conditions.

A novel organoruthenium(III) amidinate, (eta5-C5Me5)RuCl(eta-iPrN=C(Me)NiPr) (2), has been prepared by oxidation of organoruthenium amidinate, (eta5-C5Me5)Ru(eta-iPrN=C-(Me)NiPr) (1), by organic chlorides; both 1 and 2 are found to be good catalysts for atom-transfer cyclization of N-allyltrichloroacetamides which are useful for successful preparation of a pyrrolizidine alkaloid skeleton under mild conditions.

Journal Article↗
PubMed2004

Amidine nitrosation.

The acidic nitrosation chemistry of nine acyclic secondary and tertiary amidines (Ph-N=C(R(1))NR(2)R(3); R(1) = H, CH(3), Ph; R(2), R(3) = H, Ph or (CH(3))(2) or C(CH(2))(4)) and several N-acylamidines was investigated. The principal nitrosation products were amides derived from the amino moiety and compounds derived from the benzenediazonium ion, which was independently trapped for quantitation in several cases. Tertiary amidines also produce nitrosamines in minor, but significant, yields. The benzamidines did not react, and the N-acylamidines hydrolyzed much more rapidly than they nitrosated. The data support the hypothesis that the reaction occurs by nitrosation on the imino nitrogen, followed by the addition of H(2)O to give a tetrahedral intermediate (alpha-hydroxynitrosamine) for which the main decomposition pathway generates an amide and a diazonium ion. In the case of the pyrrolidine-derived amidines, about 25% of the decomposition results in cleavage of the amine moiety, which nitrosates to give N-nitrosopyrrolidine. Pseudo-first-order rate constants for amidine nitrosation in aqueous acetic acid with excess nitrite at 25 degrees C ranged from (3 to 106) x 10(-5) s(-1), while the amidine basicity ranged over 5 pK(a) units. Rate constants corrected for amidine basicity showed the pyrrolidine derived amidines to be most reactive. The lack of benzamidine nitrosative reactivity is attributed to a very slow rate of H(2)O additon to the N-nitrosoamidinium ion and reversible nitrosation.

Amides↗
PubMed2002

Reduction of N-hydroxylated compounds: amidoximes (N-hydroxyamidines) as pro-drugs of amidines.

In order to examine the importance of metabolic cycles and in particular of reductions of N-hydroxylated compounds, the reversible metabolism at the amidine, guanidine, and amidinohydrazone nitrogen atoms of various drugs and model compounds was investigated. Many of these N-oxygenated metabolites are very easily reduced back into the starting materials. A comparison of the kinetic data for the N-hydroxylation and reduction suggests that the reduction should predominate in vivo. This could be verified by in vivo studies. Thus, N-hydroxylated amidines (amidoximes) can be used as pro-drugs of amidines. Because of their strong basicity, amidines, guanidines, and amidinohydrazones are protonated under physiological conditions, are very hydrophilic, and are usually not absorbed from the gastrointestinal tract. The N-hydroxylated derivatives of amidines (amidoximes), guanidines (N-hydroxyamidines), and amidinohydrazones (N-hydroxyamidinohydrazones) are less basic because of the introduction of the oxygen atom. They are absorbed from the gastrointestinal tract and then reduced to the active amidines, guanidines, and amidinohydrazones. The pro-drug principle was originally developed in our laboratory for pentamidine and then applied to other amidines such as sibrafiban and melagatran (ximelagatran). The enzymatic basis of N-oxidative processes is very well understood, whereas reductions have been less extensively investigated. We purified an enzyme system from pig and human liver consisting of cytochrome b5, its reductase, and a P450 enzyme, which is involved in the reduction of the N-hydroxylated compounds. Similar activities were found in all species studied so far. Furthermore, comparable reductive reactions could also be demonstrated with microsomal fractions from organs other than liver. In addition, mitochondria are highly capable of performing the reductions of these N-hydroxylated compounds. Thus, several organs and cell organelles are involved in the reduction explaining the extensive reduction of the pro-drugs in vivo underlying the suitability of the concept for drug development.

Amidines↗
PubMed1975

[Studies on the osmotic resistance and the viability of amidinated erythrocytes].

The present studies are concerned with properties of amidinated erythrocytes. The reactions of dimethyladipimidate with proteins in solution and red blood cells, respectively, result in an intermolecular cross-linking. Following an amidination of human serum albumin or human gamma-globulin cross-linked products of increased molecular weight have been demonstrated by polyacrylamide gel and immune electrophoresis. Human erythrocytes previously amidinated intensely, exhibit a restricted motility of membrane particles and cross-linked hemoglobin. Intensely amidinated erythrocytes are resistant against distilled water, and they do no longer agglutinate. The findings presumably indicate an increased permeability of the amidinated red cell membrane. The glycolytic activity was found to be normal in moderately amidinated erythrocytes. In comparison with normal red blood cells, previously moderately amidinated erythrocytes of the rat become sequestered more quickly after re-injection into the vascular system.

Amidines↗
PubMed2000

EPC syntheses and structure-activity relationships of hypoglycaemic semicyclic amidines.

A series of homochiral sterically hindered mono- and bicyclic amidines was prepared as hypoglycaemic agents by lethargic reaction of O-methylcaprolactim and 3-ethoxy-2-azabicyclo[2.2.2]oct-2-ene, respectively, with homochiral cis-2-substituted cyclopentane amines provided by asymmetrical reductive amination of racemic 2-substituted cyclopentanones. All compounds, except the cyclohexylmethyl-isoquinuclidone derivative which inhibited secretion at 100 microM, significantly stimulated insulin secretion 2-8-fold at 10 microM and 100 microM in INS-1 cells. The most potent activator was the 2-cyclopentyl-substituted caprolactam derivative 5e. The stimulatory effects on secretion increased with rising steric hindrance of both the amidine alpha-carbon and the bicyclic amidine moiety itself. Enantiomeric discrimination was observed for the 2-¿(cis-2-bulkysubstituted cyclopentyl)iminohexahydroazepine halides 5e and 5f and for the 3-¿(cis-2-substituted cyclopentyl)imino-2-azabicyclo¿2.2.2ŏctane halides 6a and 6c. The amidines depolarized INS-1 cells and generated action potentials, accompanied by a decrease of membrane conductance. Simultaneously [Ca(2+)](i) increased, probably due to Ca(2+)-entry through voltage-dependent Ca(2+)-channels. At high concentrations, where inhibition of secretion was observed, ¿Ca(2+)(i) still rose upon application of the amidines, indicating an additional inhibitory pathway downstream to the elevation of ¿Ca(2+)(i). Even at high concentrations (100 microM), the amidines had no toxic effects on insulin secreting INS-1 cells.

Amidines↗
PubMed1975

Effect of amidination of lysyl residues on the oxygen affinity of human hemoglobin. Specificity of methyl acetimidate for lysine C5(40)alpha.

Treatment of human oxyhemoglobin with methylacetimidate results in selective amidination of the epfilon-amino group of lysin C5(40)alpha. The modified hemoglobin exhibits increased oxygen affinity, high cooperatively, and normal Bohr effect. Hybrid molecules containing amidinated beta chains and normal alpha chains have normal ligand-binding properties, whereas hybrid molecules containing amidinated alpha chains have ligand-binding properties identical with fully amidinated hemoglobin. Amidination of deoxyhemoglobin produces only minimal changes in ligand-binding properties. We propose that amidination of lysine C5(40)alpha prevents its participation in the salt bond with histidine HC3(146)beta in deoxyhemoglobin, thus shifting the allosteric equilibrium in favor of the high affinity oxy conformation.

Amino Acid Sequence↗
PubMed1990

Specific adsorption of serine proteases on coated silica beads substituted with amidine derivatives.

Amidine derivatives interact with serine proteases, the inhibition being due to interactions between amidine functions and the active sites of the enzymes. Five different types of amidine (substituted or unsubstituted) were coupled to coated silica beads, which had previously been coated with DEAE-dextran to minimize the non-specific interactions due to silanol groups. Coated silica functionalized with substituted amidines shows a strong affinity towards human plasmin. This affinity is probably due to hydrophobic interactions between the substituted amidine and the human plasmin structure. Coated silica grafted by p-aminobenzamide gives a specific interaction with human plasmin. The importance of ionic strength and the steric conformation of the ligand is discussed. This support was used to purify thrombin from crude preparations by high-performance affinity chromatography.

Adsorption↗
PubMed1984

Histamine H2 receptor antagonists. 1. Synthesis of N-cyano and N-carbamoyl amidine derivatives and their biological activities.

A large number of N-cyano amidine derivatives were prepared as potential histamine H2 receptor antagonists and evaluated for their inhibitory action on histamine-stimulated chronotropic response of isolated right atria from guinea pigs. Several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Of these compounds, furan (8c) and [(diaminomethylene)amino]thiazole derivatives (16c) were found to be more potent than cimetidine in both assays. In contrast to the guanidine series, methyl substitution at the terminal nitrogen of the cyano amidines was detrimental to the activities. Furthermore, acid hydrolysis of the cyano amidines gave carbamoyl amidines, which proved to be more active than the cyano amidines, the converse of the case for guanidines. 3-[[[2-[(Diaminomethylene)amino]-4- thiazolyl]methyl]thio]-N'-carbamoylpropionamidine (16d) was the most potent of all the compounds tested and was approximately 30 times more active in vitro and 50 times more active in vivo than cimetidine.

Amidines↗
PubMed2003

Amidines derived from Pt(IV)-mediated nitrile-amino alcohol coupling and their Zn(II)-catalyzed conversion into oxazolines.

The reaction between the platinum(IV) complex trans-[PtCl(4)(EtCN)(2)] and the amino alcohols NH(2)CH(2)CH(2)OH, NH(2)CH(2)CH(Me)OH-(R)-(-), NH(2)CH(Ph)CH(2)OH-(R)-(-), NH(2)CH(Et)CH(2)OH-(R)-(-), NH(2)CH(Et)CH(2)OH-(S)-(+), and NH(2)CH(Pr(n)())CH(2)OH proceeds rapidly at room temperature in CH(2)Cl(2) to furnish the amidine complexes [PtCl(4)(HN=C(Et)NH(arcraise;)OH)(2)] (1-6) in good yield (70-80%). The related reaction between the platinum(II) complex trans-[PtCl(2)(EtCN)(2)] and monoethanolamine in a molar ratio of 1:2 in CH(2)Cl(2) results in the addition of 4 equiv of NH(2)CH(2)CH(2)OH per mole of complex to give [Pt(HN=C(Et)NHCH(2)CH(2)OH)(2)(NH(2)CH(2)CH(2)OH)(2)](2+) (7). Formulation of 1-6 is based upon satisfactory C, H, N elemental analyses, electrospray mass spectrometry, IR spectroscopy, and (1)H, (13)C((1)H), (15)N, and (195)Pt NMR spectroscopies, while the structures of trans-[PtCl(4)((Z)-NH=C(Et)NHCH(2)CH(2)OH)(2)] (1), trans-[PtCl(4)((Z)-NH=C(Et)NHCH(2)CH(Me)OH-(R)-(-))(2)] (2), and trans-[PtCl(4)((Z)-NH=C(Et)NHCH(Et)CH(2)OH-(R)-(-))(2)] (4) were determined by X-ray single-crystal diffraction. The Z-amidine configuration of the ligands is preserved in CDCl(3) solutions as confirmed by gradient-enhanced (15)N,(1)H-HMQC spectroscopy and NOE experiments. The amidines, formed upon Pt(IV)-mediated nitrile-amino alcohol coupling, were liberated from their platinum(IV) complexes 1, 3, and 4 by reaction with Ph(2)PCH(2)CH(2)PPh(2) (dppe) giving free NH=C(Et)NHCHRCH(2)OH (R = H 8, Et 9, Ph 10), with the substituents R of different types, and dppe oxides; the P-containing species were identified by (31)P((1)H) NMR spectroscopy. NOESY spectroscopy indicates that the liberated amidines retained the same configuration relative to the C=N double bond, i.e., syn-(H,Et)-NH=C(Et)NHCHRCH(2)OH. The liberated hydroxo-functionalized amidines 8-10 were converted into oxazolines (11-13) in the presence of a catalytic amount of ZnCl(2). A similar catalytic effect has also been reached using anhydrous MSO(4) (M = Cu, Co, Cd), CdCl(2), and AlCl(3).

Journal Article↗
PubMed1997

Human immunodeficiency virus type-1-specific immune responses induced by DNA vaccination are greatly enhanced by mannan-coated diC14-amidine.

Use of mannan-coated N-t-butyl-N'-tetradecyl-3-tetradecylamino-propionamidine (diC14-amidine) as an adjuvant for a DNA vaccine encoding glycoprotein 160 of human immunodeficiency virus type-1 (HIV-1) enhanced the antigen-specific immune responses. The role of interferon-gamma (IFN-gamma) and interleukin-12 in the mechanism of adjuvant action was also evaluated. Coating of diC14-amidine with mannan significantly augmented the HIV-specific delayed-type hypersensitivity reaction induced by the immunogenic DNA. HIV-1-specific cytotoxic T lymphocyte activity was also markedly enhanced by the mannan-diC14-amidine cocktail. An immunomodulatory effect of this cocktail was inhibited by treatment with anti-IFN-gamma monoclonal antibody in vivo, which suggests that IFN-gamma plays an important role in inducing cell-mediated immunity by the DNA vaccine containing this adjuvant. The results of both antigen-specific immunoglobulin isotype analysis and cytokine measurement showed that the immunogenic DNA incorporated into mannan-coated diC14-amidine elicits Th1-biased immune responses.

AIDS Vaccines↗
PubMed1995

Amidines are potent inhibitors of nitric oxide synthases: preferential inhibition of the inducible isoform.

We evaluated the ability of simple alkyl amidines to inhibit the activity of the inducible isoform of nitric oxide (NO) synthase in vitro. In immunostimulated J774 macrophages, 2-iminopiperidine (EC50 = 10 microM) and butyramidine (EC50 = 60 microM) were more potent than NG-methyl-L-arginine (EC50 = 70 microM) in inhibiting nitrite formation. The five amidines tested for their ability to inhibit the conversion of L-arginine to L-citrulline by bovine endothelial cell homogenates (a source of the constitutive, endothelial NO synthase isoform) were less effective than NG-nitro-L-arginine or NG-methyl-L-arginine. The rank-order of the potencies of the amidines against the endothelial NO synthase was, in general, similar to the rank-order of the pressor effects of these agents in anesthetized rats. Thus, certain amidines are potent inhibitors of NO synthase, and are more selective towards the inducible NO synthase than the commonly used L-arginine based NO synthase inhibitors.

Amidines↗
PubMed2003

Effect of amidine derivatives on nitric oxide production by Leishmania amazonensis promastigotes and axenic amastigotes.

The effects of pentamidine isethionate (reference drug) and N,N'-diphenyl-4-methoxy-benzamidine (test compound) on NO. production by Leishmania amazonensis promastigotes and axenic amastigotes were investigated by measuring nitrite, a by-product of nitric oxide released into culture supernatants. The NO. production by infective promastigotes was inhibited by OCH(3)-amidine in about 23.53% and by pentamidine in only 3.78%. In axenic amastigotes, the inhibition of NO. production by OCH(3)-amidine was significantly higher (52.94%; p=0.01) than that by pentamidine, which inhibited this radical production nonsignificantly (25.29%; p=0.1). The mechanism of amidine derivatives, as an antimicrobial agent, is unknown. However, other amidines, such as a diamidine (pentamidine), contain chemical structures shared by the guanidino group of the nitric oxide synthase substrate L-arginine, suggesting the possibility of an interaction with this enzyme or electronic factors (substituent constant) that alter physical and chemical properties significant for biological activity.

Amidines↗
PubMed1989

Synthesis and copper-dependent antimycoplasmal activity of 1-amino-3-(2-pyridyl)isoquinoline derivatives. 2. Amidines.

In our search for new compounds with antimycoplasmal activity, a series of aromatic amidines derived from 1-amino-3-(2-pyridyl)isoquinoline (1) was synthesized. In the presence of 40 microM copper the most active compounds show growth inhibition of Mycoplasma gallisepticum in the nanomolar range. These compounds are 3 times as active as tylosin, an antimycoplasmal therapeutic agent that is used in veterinary practice. In the presence of copper, amidines derived from 1 are 2-3 times more active than the corresponding amides. Furthermore it was established that for these compounds too, the presence of a 2,2'-bipyridyl moiety is a necessary prerequisite for antimycoplasmal activity. As for the amides, antimycoplasmal activity of amidines derived from 1 is dependent on the hydrophobic fragmental value of the aromatic nucleus of the amidine moiety. A quantitative structure-activity relationship established the optimal hydrophobic fragmental value of this part of the molecule to be zero.

Amidines↗
PubMed1990

Synthesis and biological evaluation of new antimuscarinic compounds with amidine basic centers. A useful bioisosteric replacement of classical cationic heads.

Amidines (guanidine, formamidine, and acetamidine) were introduced as substitutes for the cationic heads present in atropine, scopolamine, and corresponding quaternary derivatives. Amidine systems are intermediate in structure between tertiary amines and quaternary compounds, at least as regards ionization and electronic properties, but differ from the latter in shape (planar not tetrahedral). They have additional binding opportunities on account of their hydrogen-bond-forming capacity. The effect of the introduction of these cationic heads on the affinity for different muscarinic acetyl choline receptor (m-AcChR) subtypes was investigated in vitro, in binding displacement studies, and in functional tests on isolated organs. All new compounds (3a,b-5a,b) showed high affinity for the m-AcChR considered, comparable or slightly inferior to that of the parent drugs (1a-e). The new amidine derivatives proved effective as spasmolytic agents, with little tendency to cause central effects. However, no separation was achieved of spasmolytic and other untoward effects, like inhibition of salivation. Thus, amidine moieties are effective bioisosteric substitutes for conventional cationic heads present in antimuscarinic agents. Their unusual physical-chemical properties make them useful tools when modulation of pharmacokinetic or pharmacodynamic effects is required.

Amidines↗
PubMed1987

Studies on histamine H2 receptor antagonists. 2. Synthesis and pharmacological activities of N-sulfamoyl and N-sulfonyl amidine derivatives.

A series of N-sulfamoyl and N-sulfonyl amidines have been prepared and tested in vitro for H2 antihistamine activity on guinea pig atrium. In addition, several selected compounds were assessed as inhibitors of gastric acid secretion induced by histamine in anesthetized dogs. Structure-activity relationship studies showed that those compounds containing 2-[(diaminomethylene)amino]thiazole exhibited potent H2-receptor antagonist activity. Introduction of alkyl or aralkyl groups to the terminal nitrogen of the sulfamoyl moiety reduced biological activities. Sulfamoyl amidines were more potent in both tests than sulfonyl amidines. Of these compounds, 3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]- N2-sulfamoylpropionamidine (2e, famotidine) showed extremely high potency in both assays and was selected for clinical trials as an antiulcer agent. Acid-catalyzed hydrolysis of famotidine gave the sulfamoyl amide 6 at room temperature and the carboxylic acid 7 at elevated temperatures. 15N NMR spectrum showed that famotidine in solution existed in only one of several possible tautomers derived from the amidine and the guanidine moieties. Nitrosation of famotidine was performed under mild condition and proved to occur on the 5-position of the thiazole ring.

Amidines↗
PubMed1987

On the structure-activity relationship of histamine H2-receptor antagonists based on the X-ray crystal structures and 1H-NMR spectra of amidine derivatives.

The conformation of six amidine compounds, which possess a common 3-[(4-thiazolyl)methylthio]propionylamidine framework but exhibit different activities as histamine H2-receptor antagonists, have been subjected to both single crystal X-ray structural and 1H-NMR analyses. The X-ray studies suggest a correlation between antagonist activity and the relative spatial orientation of the thiazolyl and amidine nitrogen atoms. This correlation is supported by a comparison of the conformations observed for the amidines with those of other H2-receptor antagonists and reveal that a folded conformation, specifically the NH...N intramolecular hydrogen-bonded configuration, is important for antagonist activity. The 1H-NMR measurements on the active amidine compounds show that the intramolecular NH...N bond is likely to be present in solution.

Amidines↗
PubMed1996

Occurrence of Neighboring Group Participation Reactions in Amide-N and Amidine Complexes Derived from Pentaammine(dinitrile)cobalt(III) Ions.

N-Bonded pentaamminecobalt(III) complexes of 2-cyanobenzamide, 2-cyanoacetamide, and fumaric, succinic, glutaric, and adipic amide-nitriles have been prepared. The kinetics of the base hydrolysis of (succinonitrile)pentaamminecobalt(III) have been measured: k(obsd) = k(OH) [OH(-)]; k(OH) = 1.23 x 10(3) {I = 1.00 M (NaCH(3)COO), 25 degrees C}. Amido-N-coordinated 2-cyanobenzamide cyclized in aqueous base, and it forms [(1-oxo-3-iminoisoindolino-endo-N)pentaamminecobalt(III). In aqueous acid it protonates on the exo-imine and solvolyzes (k(H) = 7.9 x 10(-)(5) s(-)(1)), forming the pentaammineaquacobalt(III) complex and 1-oxo-3-iminoisoindoline. In aqueous acid the amido-N complexes are protonated on the amide oxygen. The 2-cyanobenzamide species rearranges to form the nitrile-bonded linkage isomer in aqueous acid and also in Me(2)SO-d(6), while the succinic amide nitrile complex rearranges more slowly in aqueous acid to form solely the nitrile-bonded linkage isomer. The kinetics of the reaction were k(obsd) = f(k(H)[H(+)]/(K(a) + [H(+)])) where k(H) = 3.4 x 10(-)(4) M(-)(1) s(-)(1) and K(a) = 6.76 x 10(-)(2) M, pK(a) 1.2; pK(a) 1.3 (spectrophotometric) {I = 1.00 M (LiClO(4).3H(2)O), 25 degrees C}. In Me(2)SO-d(6) this amide-N complex reacts by three pathways: solvolysis, amide-N to -O isomerization, and amide-N to nitrile-bonded rearrangement (10%). The conjugate acid of the 2-cyanoacetamido-N complex reacted in both aqueous acid and acidified Me(2)SO-d(6) by solvolysis, amide N to O isomerization, and amide-N to nitrile-bonded rearrangement (17% in each solvent). The fumaric, glutaric, and adipic amide-nitrile complexes bonded through the amide nitrogen react only by solvolysis and amide-N to -O isomerization. Pentaamminecobalt(III) complexes of 2-cyanobenzamidine and succinic, glutaric, and adipic amidine-nitriles bonded through the amidine secondary nitrogen have been prepared. The 2-cyanobenzamidine complex undergoes rapid ligand cyclization to form the corresponding complex of 1,3-diiminoisoindoline bonded through the deprotonated endocyclic nitrogen. In aqueous acid the complex is protonated on one of the exo-imines, and this solvolyzes to form the pentaammineaquacobalt(III) complex and 1,3-diiminoisoindoline {k(H) = 1.7 x 10(-)(3) s(-)(1) (0.5 M HCl, 25 degrees C). Coordinated succinic amidine-nitrile also cyclizes in liquid ammonia to yield the complex of 2,5-diiminopyrrolidine bonded through the deprotonated endocyclic nitrogen. This is stable in aqueous base but solvolyzes rapidly (t(1/2) (s)) in aqueous acid to the aqua complex and succinimide; the latter is formed by hydrolysis of the free 2,5-diiminopyrrolidine. The dinuclear complex &mgr;-decaammine(succinonitrile)dicobalt(III) was synthesized; in aqueous base it forms &mgr;-(succinamido-N)decaamminecobalt(III). The dinuclear dinitrile complex reacts in liquid ammonia to form the corresponding succinic amidine-nitrile species which cyclizes rapidly to form &mgr;-decaammine(2,5-diiminopyrrolidino)cobalt(III) in which the ligand is bonded to cobalt(III) through the exo-imines.

Journal Article↗