Schiff Base Products Research Articles

Synthesis, Characterization and Antimicrobial activity Study Via some new Schiff bases for Trimethoprim

This search reports the synthesis of some new series of Schiff base compounds for trimetheprim derivatives which known high been known as a medicinal effectiveness. Trimetheprim was condensed with several substituted aldehydes compounds.(4-dimethyl amine benzaldehyde , propanal , salicaldehyde, 2.4 dimethoxy benzaldehyde and 4- methyl benzaldehyde) to obtain Schiff base products(1a-5a) and several substituted ketones compound (4-aminoacetophenone,4-chloroacetophenone, isobutyleketone, acetylacetone and acetophenone) to obtain Schiff base products(6b-10b) in ethanol in the presence of concentrated sulphuric acid as a catalyst to yield the Schiff base. The structure of synthesized compounds has been established on the basis of their Chemical structures of all products were confirmed by spectrophotometric methods such as U.V. visible and FTIR.. All these compounds were evaluated for their antibacterial activity in vitro against Gram + ve bacteria (bacillus) , Gram –ve bacteria (E-Coli).Most Compound under investigation exhibited potent antibacterial activity

X-ray observation of a transient hemiaminal trapped in a porous network

X-ray crystallography is the method of choice for the direct structural analysis of crystalline compounds. Extending its use to the in situ mapping of chemical transformations could provide valuable insights, as illustrated by time-resolved X-ray crystallography studies; however, the transient nature of unstable reaction intermediates often poses a significant challenge. It has recently been demonstrated that standard chemical reactions can occur within the pores of porous coordination networks and that the robust crystallinity of these networks facilitates in situ X-ray analysis of the adducts and products. Here we show that such systems even enable X-ray observations of reaction intermediates that are usually transient and non-isolable. Our proof-of-concept demonstration examines the simple and ubiquitous reaction between an amine and an aldehyde, which normally form a very short-lived hemiaminal that then yields the Schiff-base product. The mechanism of this reaction has been exhaustively examined, but the hemiaminal intermediate has only rarely been observed. We first determine the structure of a porous network with an aromatic amine embedded in it, then diffuse an aldehyde substrate into the material to transform the amine into a hemiaminal intermediate that is kinetically trapped and thus amenable to X-ray analysis, and finally raise the temperature of the system to obtain the imine product and determine its structure. These results establish that porous network materials provide a means of obtaining sequential X-ray-based snapshots of the structural transformations that occur during chemical reactions.

Lipid peroxidation products in human spermatozoa: detection and pathogenic significance.

Products of lipid peroxidation (Schiff-base products were detected in normal human spermatozoa. During aerobic incubation of the spermatozoa with an oxidant (ferrous sulphate) the peroxides became detectable in increased concentration. Coincidentally with the formation of peroxides the sperm motility declined.

Efficient, Mild and One Pot Synthesis of N,N'-Bis(salicylidene)arylmethanediamines via Three Component Reaction under Solvent Free Conditions

An economical and environmental friendly method has been developed for the synthesis of N,N'-bis(salicylidene)-arylmethanediamine derivatives. This procedure were carried out through one pot three component reaction of two different aromatic aldehydes and ammonium acetate salt in the presence of a base under free solvent conditions at room temperature. The Schiff base products were purely obtained in excellent yields and short reaction times.

Unexpected Schiff-base complex formation from the oxidation reaction of a nickel(II) complex with the meso-HMPAO ligand by molecular oxygen

The synthesis and characterization of the amine–oxime complex [Ni( meso-HMPAO)–H] · ClO 4 ( 1) and its oxidized Schiff-base product [Ni( meso-HMPAO)-5H] · ClO 4 ( 2), where HMPAO is hexamethyl propylene amine oxime, are presented. Complex 2 results from the oxidation of 1 by molecular oxygen in basic aqueous solution. The structural change of the amine complex 1 to the Schiff-base complex 2 was investigated by the means of NMR spectroscopy and X-ray crystallography.

Synthesis and structure–activity relationships of metal–ligand complexes that potently inhibit cell migration

We screened the National Cancer Institute Diversity Set compound collection for small molecules that affect mammalian cell migration and identified NSC 295642 as an inhibitor of cell motility with nanomolar potency. We found by LC–MS and X-ray crystallography that NSC 295642, a Cu(II) complex of the Schiff base product of condensation of S-benzyl dithiocarbazate and 2-acetylpyridine, has a bridged dimeric Cu 2Cl 2(L) 2 structure with distorted square pyramidal geometry. Each of the two copper atoms is five-coordinated to one of the two tridentate chelating ligands and both bridging chlorine atoms. To define structure–activity relationships, we investigated the bioactivity of related metal–ligand complexes derived from different metal(II) atoms and different ligands. Complexation of the NSC 295642 ligand with Zn(II) or Ni(II), delivered as metal(II) chloride salts under conditions identical to those used for preparation of the original Cu(II) complex, instead results in distorted octahedral bis-chelate structures, where a single metal atom is six-coordinated to two ligands. The Zn(L) 2 complex possesses a potency similar to that of the Cu 2Cl 2(L) 2 complex, while the Ni(L) 2 has no antimigratory activity at all. We carried out density functional theory calculations to obtain the electronic ground state geometry of the complexes, both in vacuum and implicit water solvent. The X-ray crystal and energy-minimized structures are very similar and exhibit a transoid orientation of the S-benzyl groups relative to the central metal-coordinated rings for both of the bioactive Cu 2Cl 2(L) 2 and Zn(L) 2 complexes, despite their different coordination geometries. In contrast, the biologically inactive Ni(L) 2 complex adopts a cisoid conformation. Varying the ligand structure, we found that hydrophobic S-alkylaryl groups are required for activity. Complexes with a simple S-methyl group, S-benzyl groups with polar substitutions or a carboxylated pyridine ring exhibit dramatically reduced activity. We tested the most potent metal–ligand complex in a number of cancer cell lines and found cell-type selectivity in its effect on cell motility. Collectively, these results suggest that a two-ligand structure with bulky nonpolar S-substituents in a transoid conformation is important for the antimigratory activity of these metal–ligand complexes.

Lipid Peroxidation Products Inhibit Dopamine Catabolism Yielding Aberrant Levels of a Reactive Intermediate

Recent work indicates that oxidative stress is a factor in Parkinson's disease (PD); however, it is unknown how this condition causes selective dopaminergic cell death. The neurotransmitter dopamine (DA) has been implicated as an endogenous neurotoxin to explain the selective neurodegeneration. DA undergoes catabolism by monoamine oxidase (MAO) to the reactive intermediate 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is further oxidized to 3,4-dihydroxyphenylacetic (DOPAC) acid via mitochondrial aldehyde dehydrogenase (ALDH). Previous studies found DOPAL to be more toxic than DA, and the major lipid peroxidation products, that is, 4-hydroxynonenal (4HNE) and malondialdehyde (MDA), potently inhibit ALDH. The hypothesis of this work is that lipid peroxidation products inhibit DOPAL oxidation, yielding aberrant levels of the reactive aldehyde intermediate. Treatment of striatal synaptosomes with 2-100 microM 4HNE or 2-50 microM MDA impaired DOPAL oxidation, resulting in elevated [DOPAL]. The aberrant concentration of DOPAL yielded an increase in protein modification by the DA-derived aldehyde, evident via staining of proteins with nitroblue tetrazolium (NBT). Pretreatment of synaptosomes with an MAO inhibitor significantly decreased NBT staining. On the basis of NBT staining, the order of protein reactivity for DA and metabolites was found to be DOPAL>>DOPAC>DA. Mass spectrometric analysis of a model peptide reacted with DOPAL revealed the adduct to be a Schiff base product. In summary, these data demonstrate the sensitivity of DA catabolism to the lipid peroxidation products 4HNE and MDA even at low, physiologic levels and suggest a mechanistic link between oxidative stress and generation of aberrant levels of an endogenous and protein reactive dopaminergic toxin relevant to PD.

Structural properties of cyclopentanone-bridged bis-macrocyclic ligand dicopper(II) complexes in the solid and in solution: a successful test of the MM-EPR method.

The copper(II)-assisted condensation of 2,3,2-tet (3,7-diazanonane-1,9-diamine) with formaldehyde and cyclopentanone yields the mono- and bis-macrocyclic Mannich condensation products L(1) and L(2), as well as the Schiff-base product L(3), all with cyclam-type tetraaza macrocycles, coordinated to copper(II). The combination of molecular mechanics and EPR spectroscopy (MM-EPR) reveals that all three isomers of [Cu(2)(L(2))(OH(2))(n)](2+) (n = 0-4), with the expected trans-III (R,R,S,S) configuration of the 14-membered tetraaza macrocycles, are of similar stability, and that the isomer whose structure is solved by X-ray crystallography has a different structure in solution.

Effect of pH on a gossypol complex with phospholipids: Gossypol‐PE

AbstractPE, one of the major phospholipids in oilseed soapstock, may react with gossypol to form Schiff bases. PE amounts to 20–30% of the phosphorus compounds in soap‐stock. In this report, the dependence on pH of the Schiff base products between PE and gossypol was investigated using a spectrophotometer, an HPLC equipped with an ELSD, and an LC‐MS system. We observed that at pH 7 the Schiff reaction product and reactants were clearly detected by ELSD, absorption, and LC‐MS spectra. The absorption spectra displayed the characteristic peak for the Schiff bases around 430–440 nm. The absorption spectra also indicated that the reaction was pH dependent. The reaction temperatures were 60 and 90°C. The LC‐MS spectra supported the formation of Schiff bases as well as methyl ether derivatives of gossypol in alcohol at the elevated temperatures. The implications of these experimental findings are presented in this paper.

Correlation of Antiphospholipid Antibody Recognition with the Structure of Synthetic Oxidized Phospholipids: IMPORTANCE OF SCHIFF BASE FORMATION AND ALDOL CONDENSATION

The oxidation of low density lipoproteins (LDL) has been correlated with atherogenesis through a variety of pathways. The process involves nonspecific fragmentation, oxidative breakdown, and modification of the lipids and protein of LDL. The process yields a variety of bioactive products, including aldehyde-containing phospholipids, which can cross-react with primary amines (i.e. peptides or phospholipid head groups) to yield Schiff base products. We also demonstrate that such oxidized phospholipid products may further react through a post-oxidation chemical pathway involving aldol condensation. EO6, an IgM monoclonal autoantibody to oxidized phospholipids, blocks the uptake of oxidized LDL (OxLDL) by macrophages. Because the epitope(s) of EO6 also blocks the uptake of OxLDL, a series of oxidized phospholipids, their peptide complexes, and their aldol condensates have been synthesized and characterized, and their antigenicity has been determined. This study defines structural motifs of oxidized phospholipids responsible for antigenicity for EO6. Certain monomeric phospholipids containing short chain fatty acids were antigenic whether oxidized or not in the sn-2 position. However, oxidized phospholipids containing sn-1 long chain fatty acids were not antigenic unless the sn-2 oxidized fatty acid contained an aldehyde that first reacted with a peptide yielding a Schiff base or the sn-2 oxidized fatty acid underwent an aldol type self-condensation. Our data indicate that the phosphorylcholine head group is essential for antigenicity, but its availability depends on the oxidized phospholipid conformation. We suggest that upon oxidation, similar reactions occur in phospholipids on the surface of LDL, generating ligands for macrophage recognition. Synthetic imine adducts of oxidized phospholipids of this type are capable of blocking the uptake of OxLDL.

Helical peptide models for protein glycation: proximity effects in catalysis of the Amadori rearrangement

Introduction: Non-enzymatic glycation of proteins has been implicated in various diabetic complications and age-related disorders. Proteins undergo glycation at the N-terminus or at the ϵ-amino group of lysine residues. The observation that only a fraction of all lysine residues undergo glycation indicates the role of the immediate chemical environment in the glycation reaction. Here we have constructed helical peptide models, which juxtapose lysine with potentially catalytic residues in order to probe their roles in the individual steps of the glycation reaction. Results: The peptides investigated in this study are constrained to adopt helical conformations allowing residues in the i and i+4 positions to come into spatial proximity, while residues i and i+2 are far apart. The placing of aspartic acid and histidine residues at interacting positions with lysine modulates the steps involved in early peptide glycation (reversible Schiff base formation and its subsequent irreversible conversion to a ketoamine product, the Amadori rearrangement). Proximal positioning of aspartic acid or histidine with respect to the reactive lysine residue retards initial Schiff base formation. On the contrary, aspartic acid promotes catalysis of the Amadori rearrangement. Presence of the strongly basic residue arginine proximate to lysine favorably affects the p K a of both the lysine ϵ-amino group and the singly glycated lysine, aiding in the formation of doubly glycated species. The Amadori product also formed carboxymethyl lysine, an advanced glycation endproduct (AGE), in a time-dependent manner. Conclusions: Stereochemically defined peptide scaffolds are convenient tools for studying near neighbor effects on the reactivity of functional amino acid sidechains. The present study utilizes stereochemically defined peptide helices to effectively demonstrate that aspartic acid is an efficient catalytic residue in the Amadori arrangement. The results emphasize the structural determinants of Schiff base and Amadori product formation in the final accumulation of glycated peptides.

Membrane lipid peroxidation, nitrogen fixation and leghemoglobin content in soybean root nodules

Summary Membrane lipids in soybean nodules may undergo oxidative degradation resulting in the loss of membrane structural integrity and physiological activities. One of the final products of lipid peroxidation is malondialdehyde (MDA), which can react with thiobarbituric acid (TBA) in vitro to form a chromogenic adduct, a Schiff base product that can be measured spectrophotometrically. MDA formation was quantified in the nodules as well as in the adjacent root tissue. Lipid peroxidation was initially high in soybean nodules induced by Bradyrhizobium japonicum, but sharply declined following an increase in both leghemoglobin content and nitrogen fixation rate. Lipid peroxidation was 2 to 4 times higher in the nodules than in their corresponding adjoining root tissue. Malondialdehyde levels in ineffective nodules were 1.5 times higher than those in effective nodules. MDA formation was also shown to occur in the ‘leghemoglobin-free’ cytosolic fraction, the ‘leghemoglobin’ fraction, and the nodule tissue pellet. Antioxidants, such as reduced ascorbic acid, glutathione, and 8-hydroxyquinoline, caused a partial suppression of lipid peroxidation, whereas ferrous sulfate, hydrogen peroxide, iron EDTA, disodium-EDTA, and β-carotene induced MDA formation. In contrast, quenchers of oxygen free radicals such as HEPES, MES, MOPS, PIPES, phenylalanine, Tiron, thiourea, sodium azide, and sodium cyanide (uncouplers of oxidative phosphorylation) caused somewhere between a 12 to 70 percnt; reduction in MDA production. TBA-reactive products were formed despite the incorporation of superoxide dismutase, proxidase, and catalase into the reaction mixture.

Liquid Chromatography–Mass Spectrometry and Proton Nuclear Magnetic Resonance Characterization of Trace Level Condensation Products Formed Between Lactose and the Amine‐Containing Diuretic Hydrochlorothiazide

Trace levels of condensation products between lactose and the amine‐containing diuretic hydrochlorothiazide are formed when a mixture of the two solids containing 30% weight water is heated at 60 °C for 2 weeks. The two most abundant condensation products were characterized by liquid chromatography‐mass spectrometry (LC‐MS) and proton nuclear magnetic resonance (1H NMR) spectroscopy. Under these relatively mild conditions of formation, the amine–lactose reaction products are limited to those involving the elimination of only a single molecule of water, rather than the multiple‐water eliminations associated with later stages of the Maillard reaction. The spectroscopic data clearly show that the primary condensation products are cyclic N‐substituted glycosylamines rather than Schiff base, 1,2‐enolic forms, or Amadori rearrangement products of identical mass. In solution, the two most abundant N‐substituted glycosylamines are shown to be in a kinetically slow equilibrium with each other, most likely through a mutarotation involving the intermediate formation of the acyclic Schiff base. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 920–929, 2000

Electroactive Polymer Films Formed from the Schiff Base Product of 1,8-Diaminonaphthalene and Dehydroacetic Acid. I. Preparation and Characterization

We report on the preliminary synthesis and characterization of an electroactive, conducting polymer that should readily bind metal cation. Anodic polymerization of the Schiff base resulting from the condensation reaction between 1,8‐diaminonaphthalene and dehydroacetic acid, 8‐(3‐acetylimino‐6‐methyl‐2,4‐dioxopyran)‐1‐aminonaphthalene, on platinum electrode in acetonitrile was found to yield thin, electroactive polymeric films. The films were found electroactive in acetonitrile and aqueous sulfuric acid solution and the electroacity is attributed to the electron transformation of the amino/imine sites in the polymer as in aromatic amine polymers. Electrochemical studies of electron‐transfer reactions on the polymer‐covered platinum electrodes indicated that the polymer films are highly porous and semiconducting. © 2000 The Electrochemical Society. All rights reserved.

Lysine-69 plays a key role in catalysis by ornithine decarboxylase through acceleration of the Schiff base formation, decarboxylation, and product release steps.

Ornithine decarboxylase (ODC) is a pyridoxal-5'-phosphate-dependent (PLP) enzyme that catalyzes the biosynthesis of the polyamine putrescine. Similar to other PLP-dependent enzymes, an active site Lys residue forms a Schiff base with PLP in the absence of substrate. The mechanistic role of this residue (Lys-69) in catalysis by Trypanosoma brucei ODC has been studied by analysis of the mutant enzymes, in which Lys-69 has been replaced by Arg (K69R ODC) and Ala (K69A ODC). Analysis of K69A ODC demonstrated that the enzyme copurified with amines (e.g. putrescine) that were tightly bound to the active site through a Schiff base with PLP. In contrast, on the basis of an absorption spectrum of K69R ODC, PLP is likely to be bound to this mutant enzyme in the aldehyde form. Pre-steady-state kinetic analysis of the reaction of K69R ODC with L-Orn and putrescine demonstrated that the rates of both the product release (k(off.Put) = 0.0041 s(-)(1)) and the decarboxylation (k(decarb) = 0.016 s(-)(1)) steps were decreased by10(4)-fold in comparison to wild-type ODC. Further, the rates of Schiff base formation between K69R ODC and either substrate or product have decreased by at least 10(3)-fold. Product release remains as the dominant rate-limiting step in the reaction (the steady-state parameters for K69R ODC are k(cat) = 0.0031 s(-)(1) and K(m) = 0.18 mM). The effect of mutating Lys-69 on the decarboxylation step suggests that Lys-69 may play a role in the proper positioning of the alpha-carboxylate for efficient decarboxylation. K69R ODC binds diamines and amino acids with higher affinity than the wild-type enzyme; however, Lys-69 does not mediate substrate specificity. Wild-type and K69R ODC have similar ligand specificity preferring to bind putrescine over longer and shorter diamines. Kinetic analysis of the binding of a series of diamines and amino acids to K69R ODC suggests that noncovalent interactions in the active site of K69R ODC promote selective ligand binding during Schiff base formation.

Receptors for proteins modified by advanced glycation endproducts (AGE)—their functional role in atherosclerosis

Long-term incubation of proteins with glucose leads, through the formation of early stage products such as Schiff base and Amadori rearrangement products, to the formation of advanced glycation end products (AGE). Recent studies of AGE-structures as well as the receptor for AGE-proteins (AGE-receptors) have emphasized the involvement of protein modification by AGE in aging and age-enhanced disease processes. Immunohistochemical analyses of human atherosclerotic lesions using a monoclonal anti-AGE antibody have demonstrated diffuse extracellular AGE-deposition as well as dense intracellular AGE-deposition in macrophage- and vascular smooth muscle cell (SMC)-derived foam cells. In vitro experiments using both CHO cells overexpressing macrophage scavenger receptor-A (MSR-A) and peritoneal macrophages from MSR-A-knockout mice have shown that the MSR-A plays a major role in endocytic uptake of AGE-proteins by macrophages. Furthermore, in vitro experiments with rabbit arterial SMCs demonstrated a novel AGE-receptor mediating endocytosis of AGE-proteins. These in vivo and in vitro experiments suggest that AGE-proteins formed extracellularly in atherosclerotic lesions are endocytosed by macrophages through MSR-A in the early stage, and by SMCs through the novel AGE-receptor in the advanced stage, implicating functional contribution of the AGE-receptor-mediated interaction of AGE-proteins with these cells to atherosclerotic processes in arterial walls.

Reactions of 7- and 9-aminoadenines with 2,4-pentanedione. Formation of new ring systems, pyridazino[6,1-f]purine and pyridazino[1,6-e]purine.

Reactions of 7-aminoadenines with 2,4-pentanedione yielded pyridazino[6,1-f]purines and 5-pyrazolylpyrimidines. The structure of the latter was identified by X-ray analysis. Reaction of 9-amino-N6-methyladenine with 2,4-pentanedione gave pyridazino[1,6-e]purine and Schiff base products. Possible reaction mechanisms are discussed.

Fluorescence microscopic demonstration of cathepsin K activity as the major lysosomal cysteine proteinase in osteoclasts.

The enzyme activity of lysosomal cysteine proteinases in vital rabbit osteoclasts and mouse osteoclast-like cells was visualized with Z-Leu-Arg-4-methoxy-beta-naphthylamide (Z-LR-MNA) as the enzyme substrate. The MNA liberated by proteolysis forms a fluorescent insoluble Schiff-base product in the presence of 5-nitrosalicylaldehyde. Many small fluorescent particles, endproducts of the Z-LR-MNA hydrolysis, were observed in proximity to the bone surface underneath the actively resorbing osteoclasts, as well as in the cytoplasm. The Z-LR-MNA hydrolase activity was markedly diminished by bafilomycin A1 and chloroquine treatment. Moreover, the activity was completely inhibited by cysteine proteinase inhibitors such as leupeptin and E-64d, but not by other classes of proteinase inhibitors. About 60% of the hydrolase activity in mouse osteoclast-like cells was immunoabsorbed by anti-cathepsin K antibody-coupled Sepharose CL-4B beads, and about 10% of the activity was absorbed with the anti-cathepsin L antibody-coupled beads. Thus, the majority of the Z-LR-MNA hydrolase activity in osteoclasts was derived from cathepsin K. In contrast, using the same substrate in the assay, no detectable cathepsin K activity was observed in mouse peritoneal macrophages. The abundant cathepsin K activity in osteoclasts would therefore indicate a significant role of this enzyme in bone matrix degradation.

Modifications to the azomethine-H method for determining boron in water

In the traditional azomethine-H methods, aqueous azomethine-H solutions readily hydrolyze at near neutral pH to form salicylaldehyde and the aminonaphthol, H-acid. Long color development times have been required, during which boron catalyzes the re-condensation of the hydrolysis products to the Schiff base. As a result of these findings, a new, rapid procedure has been developed based on the boron-catalyzed condensation of salicylaldehyde and H-acid. The conditions for formation and measurement of the Schiff base product have been optimized to provide excellent selectivity and sensitivity for the determination of soluble boron in water. A possible mechanism for the boron-promoted condensation reaction is suggested.

The role of oxidative stress in the long-term glycation of LDL.

Advanced glycation is a major pathway for the posttranslational modification of plasma and tissue proteins. The initiating reaction is the nonenzymatic addition of sugars such as glucose to the primary amino groups of proteins, i.e., mainly to lysine residues. These "early" Schiff base and Amadori products then undergo a series of inter- and intramolecular rearrangements to produce the "late" products termed advanced glycation end products (AGEs). Incubation of LDL with glucose or glucose-6-phosphate produces AGE moieties on both the lipid and apolipoprotein B components. In addition, we tried to generate AGE-LDL by reaction with AGE-peptides (< 10 kD) obtained by enzymatic digestion of long-term glycated fibronectin as a model for connective tissue AGE-peptides. AGE-formation can be assessed by monitoring of fluorescence (370/440 nm) which is easily differentiated from the much lower autofluorescence of oxidized low density lipoproteins (oxLDL). Alternatively, AGE formation was detected by an AGE-specific ELISA using antibodies elicited in rabbits against bovine AGE-RNAse. In the present study we investigated the influence of oxidative stress on the long-term glycation of LDL and the modulation of LDL-oxidation by AGE-modification. We observed (a) that the rate of AGE formation is reduced by BHT/EDTA both on LDL and serum albumin (glycation vs. glycoxidation), (b) long-term glycated LDL is more readily oxidized than unglycated LDL, (c) oxLDL is more prone to AGE-modification, (d) AGE-modification of LDL strongly alters its epitope spectrum and (e) that aminoguanidine at higher concentrations (1-10 mM) inhibits copper-catalyzed LDL oxidation in the way of a classical antioxidant.