Salicylic Acid Derivatives Research Articles

A computational study for the antioxidant capacity increases in hydroxy-derivatives of paracetamol and salicylic acid

Paracetamol is a more potent antioxidant than salicylic acid on the several oxidative stress-forced models. A possible mechanism of hydroxylation by the hydroxyl radicals and their antioxidant properties was performed by molecular modeling using quantum chemical calculations at the B3LYP level of theory. The calculation was made in gas phase and water using PCM method. The electron abstraction for hydroxylated paracetamol derivatives is more favored than hydroxylated salicylic acid derivatives. The increase in antioxidant capacity is more observed for hydroxylated derivatives of the paracetamol than salicylic acid. Some hydroxylated derivatives of paracetamol and salicylic acid were more reactive than trolox by hydrogen transfer. Their antioxidant capacity can be increased by number and position of the hydroxyl group.

Palladium-catalyzed three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide

Three-component coupling reactions of 2-(cyanomethyl)phenol, aryl halides, and carbon monoxide (CO) in orthogonal–tandem catalysis were investigated. In the reactions, 2-(cyanomethyl)phenyl esters, which are produced through Pd(PPh3)4-catalyzed alkoxycarbonylation of aryl halides with 2-(cyanomethyl)phenol, undergo cycloisomerization in situ catalyzed by Pd(PCy3)2 as a co-catalyst to give 3-acyl-2-aminobenzofurans. Palladium species with homoleptic tertiary phosphines, such as Pd(PPh3)4 and Pd(PCy3)2, can catalyze the mechanistically distinct reactions in an orthogonal–tandem manner without interference. By switching the base used in this reaction, 3-acyl-2-(N-acylamino)benzofurans were obtained as major products instead of 3-acyl-2-aminobenzofurans. Given that 2-(cyanomethyl)phenols can be synthesized from commercially available salicylic acid derivatives in two steps, the present method thus provides facile access to synthetically useful 3-acyl-2-aminobenzofurans.

Crystal structure of 3-bromo-2-hy-droxy-benzoic acid.

Mutual carbox-yl-carboxyl O-H⋯O hydrogen bonds link the mol-ecules of the title compound, C7H5BrO3, into centrosymmetric dimers which display a central R 2 (2)(8) ring motif. In addition, there is an intra-molecular hydrox-yl-carboxyl O-H⋯O inter-action present. A comparison with the crystal structures of 59 other substituted derivatives of salicylic acid shows that both the centrosymmetric carbox-yl-carboxyl O-H⋯O dimer and the stacking mode of mol-ecules along the short a axis observed in the title structure are frequent packing motifs in this set.

Hybrid catalytic effects of K2CO3 on the synthesis of salicylic acid from carboxylation of phenol with CO2

As a base-promoted Kolbe–Schmitt carboxylation reaction, the mechanism of synthesis of salicylic acid derivatives from phenols with CO2 in the industry is still unclear, even up to now. In this paper, synthesis of 3,6-dichloro salicylic acid (3,6-DCSA) from 2,5-dichloro phenoxide and CO2 was investigated in the presence of K2CO3. We show the reaction can proceed by itself, but it goes at a slower rate as well as a lower yield, compared to the case with the addition of K2CO3. However, the yield of 3,6-DCSA is only minorly affected by the size of K2CO3, which cannot be explained from the view of catalytic effect. Therefore, K2CO3 may on one hand act as a catalyst for the activation of CO2 so that the reaction can be accelerated, while on the other hand, it also acts as a co-reactant in deprotonating the phenol formed by the side reaction to phenoxide, which is further converted to salicylate.

Photochemistry of Fe(III) complexes with salicylic acid derivatives in aqueous solutions

Abstract The photochemistry of a series of 1:1 Fe(III) complexes with salicylic acid derivatives (SADs) in aqueous solution has been investigated, using the following model compounds: salicylic acid (SA), 5-sulfoSA (5SSA), 4-hydroxySA (2HSA), 6-hydroxySA (6HSA), 4-nitroSA (4NSA) and 5-nitroSA (5NSA). The results of optical spectroscopy, steady-state and nanosecond laser flash photolysis experiments show that all Fe(III)–SAD complexes exhibit good photochemical stability upon 355 nm excitation (quantum yields of photolysis do not exceed 0.01). No evidence of hydroxyl radical formation was observed in laser flash experiments. Therefore, the primary photoprocess was assumed to be an electron transfer from coordinated SAD to the Fe(III) ion in the excited complex, leading to the formation of Fe(II) and the corresponding SAD phenoxy radical. SADs containing electron-withdrawing groups (4NSA, 5NSA, 5SSA) exhibit the smallest quantum yields of photolysis of the series, whereas the highest values were observed for SA and SADs containing electron-donating groups (4HSA, 6HSA). Therefore, in contrast to Fe(III)-complexes with aliphatic carboxylates, sunlight photolysis of Fe(III)–SAD complexes cannot be an effective way for the degradation of SADs in natural water systems.

Copper‐Catalyzed Cross Dehydrogenative Coupling of N,N‐Disubstituted Formamides and Phenols: A Direct Access to Carbamates

AbstractAn efficient copper‐catalyzed protocol has been developed for the synthesis of carbamates from dialkylformamides and phenols possessing directing groups such as benzothiazole, quinoline and formyl at the ortho‐position. In this chelation assisted approach, CO bond formation takes place via a cross dehydrogenative coupling (CDC) between the formyl CH of dialkylformamide and phenolic OH in the presence of copper(II)acetate/aqueous tert‐butyl hydroperoxide. Under identical reaction conditions, salicylic acid derivatives underwent amidation with the carboxylic group rather than formamidation of the phenolic OH. The use of a cheap and environmentally benign catalyst along with the tolerance of a wide range of functional groups makes this an easy, phosgene‐free route to carbamates.magnified image

Synthesis, crystal structure, spectroscopic properties and potential biological activities of salicylate‒neocuproine ternary copper(II) complexes.

Mixed ligand copper(II) complexes containing derivatives of salicylic acid and heterocyclic ligands with nitrogen donor atoms have been the subject of various studies and reviews. In this paper, synthesis and characterization of the ternary copper(II) complexes of neocuproine (2,9-dimethyl-1,10-phenanthroline, Neo) and salicylate ligands (Sal) are reported. In addition, the crystal structures of ([Cu(H2O)(5-Cl-Sal)(Neo)] (1), [Cu(μ-Sal)(Neo)]2 (2), Cu2(μ-5-Cl-Sal)(5-Cl-HSal)2(Neo)2]·EtOH (3)) were determined. In order to compare structural and biological properties of the prepared complexes, spectroscopic and biological studies were performed. Results of X-ray diffraction show that prepared complexes form three types of crystal structures in a given system: monomeric, dimeric and dinuclear complex. The preliminary study on the DNA cleavage activity has shown that the complexes under study behave as the chemical nucleases in the presence of added hydrogen peroxide with slight differences in the activity (1 > 2 > 3). The complexes 1 and 2 exhibited nuclease activity itself indicating the interaction of complexes with the DNA. It has been proposed that the enhanced destructive effect of the complexes 1 and 2 on the DNA is a result of two possible mechanisms of action: (i) the conversion of closed circular DNA (form I) to the nicked DNA (form II) caused by the copper complex itself and (ii) damage of DNA by Reactive Oxygen Species (ROS)—products of the interaction of copper with hydrogen peroxide by means of Fenton reaction (hydroxyl radicals). Thus the biological activity of the prepared Cu(II) complexes containing derivatives of salicylic acid and phenanthroline molecules is substantiated by two independent mechanisms. While derivatives of salicylic acids in the coordination sphere of copper complexes are responsible for radical-scavenging activity (predominantly towards superoxide radical anion), the presence of chelating ligand 2,9-dimethyl-1,10-phenanthroline significantly enhances capability of Cu(II) complexes binding to DNA via intercalation.

Chemical Composition of Filipendula vestita from India

(17.9%). The oil was characterized by a high content of salicylic acid derivatives, salicylaldehyde (13.7%), benzyl salicylate (6.8%), and methyl salicylate (6.7%). Moreover, n-nonanal (11.9%), 2-heptadecanone (6.2%), and linalool (5.2%) were present in significant amounts [6]. A high content of salicylaldehyde (36.0%) and methyl salicylate (19.0%) was also found in the essential oil from aerial parts of Filipendula ulmaria [7]. The essential oil composition of the root of F. vestita was analyzed and compared using capillary GC and GC-MS. The oil yields were 0.40% (v/w). The analysis led to the identification of 10 constituents forming 94.60% of the total oil composition. The identified constituents with their respective percentages and class composition are given in Table 1. The essential oil of the root of F. vestita was dominated by methyl salicylate (56.0%), salicylaldehyde (15.60%), santene (9.40%), and limonene (6.30%) as the major marker constituents, and salicylic acid butyl ester (3.40%), carvone (1.40%), benzyl salicylate (1.10%), linalool (1.40%), octenol propionate (0.50%), and (E)-asarone (0.30%) were present in trace amounts. Plant Collection, Identification, and Isolation. The fresh plant of F.vestita was collected from Milam glacier

Aspirin's Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses.

Salicylic acid (SA) and its derivatives have been used for millennia to reduce pain, fever and inflammation. In addition, prophylactic use of acetylsalicylic acid, commonly known as aspirin, reduces the risk of heart attack, stroke and certain cancers. Because aspirin is rapidly de-acetylated by esterases in human plasma, much of aspirin's bioactivity can be attributed to its primary metabolite, SA. Here we demonstrate that human high mobility group box 1 (HMGB1) is a novel SA-binding protein. SA-binding sites on HMGB1 were identified in the HMG-box domains by nuclear magnetic resonance (NMR) spectroscopic studies and confirmed by mutational analysis. Extracellular HMGB1 is a damage-associated molecular pattern molecule (DAMP), with multiple redox states. SA suppresses both the chemoattractant activity of fully reduced HMGB1 and the increased expression of proinflammatory cytokine genes and cyclooxygenase 2 (COX-2) induced by disulfide HMGB1. Natural and synthetic SA derivatives with greater potency for inhibition of HMGB1 were identified, providing proof-of-concept that new molecules with high efficacy against sterile inflammation are attainable. An HMGB1 protein mutated in one of the SA-binding sites identified by NMR chemical shift perturbation studies retained chemoattractant activity, but lost binding of and inhibition by SA and its derivatives, thereby firmly establishing that SA binding to HMGB1 directly suppresses its proinflammatory activities. Identification of HMGB1 as a pharmacological target of SA/aspirin provides new insights into the mechanisms of action of one of the world's longest and most used natural and synthetic drugs. It may also provide an explanation for the protective effects of low-dose aspirin usage.

ChemInform Abstract: Silver(I) and Gold(I)‐Promoted Synthesis of Alkylidene Lactones and 2H‐Chromenes from Salicylic and Anthranilic Acid Derivatives.

AbstractThe cycloisomerization of terminal alkynoic acids is catalyzed by Ag(I)‐ and Au(I)‐salts.

Salicylanilide diethyl phosphates as cholinesterases inhibitors

Based on the presence of dialkyl phosphate moiety, we evaluated twenty-seven salicylanilide diethyl phosphates (diethyl [2-(phenylcarbamoyl)phenyl] phosphates) for the inhibition of acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.) and butyrylcholinesterase (BChE) from equine serum. Ellman’s spectrophotometric method was used. The inhibitory activity (expressed as IC50 values) was compared with that of the established drugs galantamine and rivastigmine. Salicylanilide diethyl phosphates showed significant activity against both cholinesterases with IC50 values from 0.903 to 86.3μM. IC50s for BChE were comparatively lower than those obtained for AChE. All of the investigated compounds showed higher inhibition of AChE than rivastigmine, and six of them inhibited BChE more effectively than both rivastigmine and galantamine. In general, derivatives of 4-chlorosalicylic acid showed enhanced activity when compared to derivatives of 5-halogenated salicylic acids, especially against BChE. The most effective inhibitor of AChE was O-{5-chloro-2-[(3-bromophenyl)carbamoyl]phenyl} O,O-diethyl phosphate with IC50 of 35.4μM, which is also one of the most potent inhibitors of BChE. O-{5-Chloro-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphate exhibited in vitro the strongest inhibition of BChE (0.90μM). Salicylanilide diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors.

A new class of salicylic acid derivatives for inhibiting YopH of Yersinia pestis

Previously, we identified a class of salicylic acid derivatives that display inhibitory activity against the protein tyrosine phosphatase YopH from Yersinia pestis. Because docking study suggested that the large phenyl ring attaching to the salicylic acid core might be exposed to the solvent and might not contribute significantly to binding, we have developed a new class of compounds that no longer contain this phenyl ring. We first devised a synthetic scheme for the compounds and then developed an automated computational screening model surrounding this synthetic scheme to help select a small number of compounds for synthesis and experimental testing. Based on this computational screening model and the analysis of the structure–activity relationship of our previous class of compounds, we have synthesized eight compounds and found five that yield micromolar activity. When applying in a larger scale, the synthetic scheme and the computational screening model developed here should help to identify even more potent inhibitors in the future.

Efficient end-capping synthesis of neutral donor-acceptor [2]rotaxanes under additive-free and mild conditions.

Efficient end-capping synthesis of neutral donor-acceptor (D-A) [2]rotaxanes without loading any catalysts or activating agents was achieved by utilizing high reactivity of a pentacoordinated hydrosilane toward salicylic acid derivatives. As components of [2]rotaxanes, an electron-deficient naphthalenediimide-containing axle with a salicylic acid terminus and several electron-rich bis(naphthocrown) ether macrocycles were employed. End-capping reactions with the pentacoordinated hydrosilane underwent smoothly even at low temperature to afford the corresponding [2]rotaxanes in good yields. A [2]rotaxane containing bis-1,5-(dinaphtho)-38-crown-10 ether as a wheel molecule was synthesized and isolated in 84% yield by the end-capping at -10 °C, presenting the highest yield ever reported for the end-capping synthesis of a neutral D-A [2]rotaxane. It was found that the yields of the [2]rotaxanes in the end-capping reactions were almost parallel to the formation ratios of the corresponding pseudo[2]rotaxanes estimated by utilizing model systems. These results indicate that the end-capping reaction using the pentacoordinated hydrosilane proceeded without perturbing the threading process, and most of the pseudo[2]rotaxanes underwent efficient end-capping reaction even at low temperature.

Interactions of Scalenohedral Calcite Crystals with Acidic Amino Acid Derivatives of Salicylic Acid

The kinetics of scalenohedral calcite crystal growth in the presence of N-salicyloil-l-aspartic (N-Sal-Asp) and N-salicyloil-l-glutamic acid (N-Sal-Glu), as selected models of anti-inflammatory drug-like substances, were analyzed in order to study the molecular interactions of the selected salicylates with scalenohedral {2 1 4} surfaces. The results revealed that the growth is controlled by surface reactions, proceeding at the spiral step. The presence of the additives caused the inhibition of the growth, wherein the N-Sal-Asp interacted more strongly than N-Sal-Glu. The obtained data were supported with the electrokinetic, spectroscopic, and adsorption measurements. The interactions between the selected additives and the scalenohedral calcite crystals were compared with the rhombohedral modification. The stronger interactions of salicylates with scalenohedral surfaces are explained in terms of their higher reactivity and, most likely, better structural matching of their surface calcium ions with the sali...

5-Aminosalicylic Acid attenuates allergen-induced airway inflammation and oxidative stress in asthma

Pro-inflammatory cytokines regulate the magnitude of allergic reactions during asthma. Tumor necrosis factor – alpha (TNF-α), interleukin-6 (IL-6) and interleukin-13 (IL-13) play a crucial role in aggravating the inflammatory conditions during allergic asthma. In addition, oxidative stress contributes to the pathogenesis of asthma by altering the physiological condition resulting in the development of status asthmaticus. Anti-inflammatory corticosteroids are being widely used for treating allergic asthma. In the present study 5-aminosalicylic acid (5-ASA), a salicylic acid derivative, was evaluated, in vivo for its potential to suppress TNF-α, IL-6 and IL-13 using ovalbumin (OVA) induced allergic asthma in Balb/C mice. Oral administration of 65, 130 and 195 mg/kg 5-ASA significantly reduced the OVA induced total and differential leucocyte count, TNF-α, IL-6, IL-13, nitrite, nitrate, MDA, MPO and TPL levels in the lung lavage samples. Collectively, these findings suggest that 5-ASA is a potent immunomodulator and suppresses key Th2 cytokines production and oxidative stress in OVA-induced asthma.

English

Based on the molluscicidal activity of ginkgolic acids (GAs) isolated from Ginkgo biloba L and synthetic GA analogues, a series of long chain, substituted at 4 and 5 position, salicylic acid derivatives, including the Z/E isomers and their saturated derivatives, were prepared. Their molluscicidal activities against the host snail Oncomelania hupensis were evaluated. The acute fish toxicity against the wild-type zebrafish of saturated derivatives was tested. The results and analysis of the structural-activity relationship revealed that the E-isomers and their saturated derivatives were better molluscicidal agents than their respective Z-isomers. Molluscicidal activities were increased with the growing of the alkyl chain lengths. Acute fish toxicity test indicated that the synthesized salicylic acid derivatives were much safer than niclosamide in field use. Key words: Hydrocarbyl substituted salicylic acid derivatives, synthesis, molluscicidal activity, Oncomelania hupensis, schistosomiasis, acute fish toxicity, zebrafish.

Silver(I) and gold(I)-promoted synthesis of alkylidene lactones and 2H-chromenes from salicylic and anthranilic acid derivatives

Ag(I) and Au(I) efficiently catalyze the cycloisomerization of terminal alkynoic acids into methylene seven-membered ring lactones. Depending on the metal, divergent reaction pathways were found for non terminal alkynoic acids. While Ag(I) led to lactones, Au(I) led to 2H-chromenes coming from the hydroarylation of the alkyne.

X-ray structural analysis and antitumor activity of new salicylic acid derivatives

Tetrakis-, tris-, bis-, and mono salicylic acid derivatives 1–4 were synthesized by reaction of methyl 2-hydroxy benzoate (methyl salicylate) with 2,2-bis (hydroxymethyl) propane-1,3-diol (pentaerythritol) in the presence of sodium. Yields of different salicyloyloxy derivatives were changed by varying the molar ratios of reactants. For compounds 2 and 3, X-ray structure analysis was performed, as well as molecular energy minimization, to define their conformation in terms of their energy minima. Comparison of crystal and energy minimized structures for these two compounds (2 and 3) revealed that the intramolecular hydrogen bonds play an important role, stabilizing conformation of the most part of the molecule. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as 17β-hydroxysteroid dehydrogenase type 2 inhibition potency. Tetrakis salicyloyloxy derivative 1 expressed the highest antioxidant potency, tris salicyloyloxy derivative 2 was the best inhibitor of 17βHSD2 enzyme, while bis salicyloyloxy derivative 3 showed strong cytotoxicity against prostate and breast cancer cells with no cytotoxicity against healthy cells.

Molecular targets of aspirin and cancer prevention.

Salicylates from plant sources have been used for centuries by different cultures to treat a variety of ailments such as inflammation, fever and pain. A chemical derivative of salicylic acid, aspirin, was synthesised and mass produced by the end of the 19th century and is one of the most widely used drugs in the world. Its cardioprotective properties are well established; however, recent evidence shows that it can also act as a chemopreventive agent. Its antithrombotic and anti-inflammatory actions occur through the inhibition of cyclooxygenases. The precise mechanisms leading to its anticancer effects are not clearly established, although multiple mechanisms affecting enzyme activity, transcription factors, cellular signalling and mitochondrial functions have been proposed. This review presents a brief account of the major COX-dependent and independent pathways described in connection with aspirin's anticancer effects. Aspirin's unique ability to acetylate biomolecules besides COX has not been thoroughly investigated nor have all the targets of its primary metabolite, salicylic acid been identified. Recent reports on the ability of aspirin to acetylate multiple cellular proteins warrant a comprehensive study to investigate the role of this posttranslational modification in its anticancer effects. In this review, we also raise the intriguing possibility that aspirin may interact and acetylate cellular molecules such as RNA, and metabolites such as CoA, leading to a change in their function. Research in this area will provide a greater understanding of the mechanisms of action of this drug.

NMR-Based Metabolomic Investigation of Bioactivity of Chemical Constituents in Black Raspberry (Rubus occidentalis L.) Fruit Extracts

Black raspberry (Rubus occidentalis L.) (BR) fruit extracts with differing compound profiles have shown variable antiproliferative activities against HT-29 colon cancer cell lines. This study used partial least-squares (PLS) regression analysis to develop a high-resolution (1)H NMR-based multivariate statistical model for discerning the biological activity of BR constituents. This model identified specific bioactive compounds and ascertained their relative contribution against cancer cell proliferation. Cyanidin 3-rutinoside and cyanidin 3-xylosylrutinoside were the predominant contributors to the extract bioactivity, but salicylic acid derivatives (e.g., salicylic acid glucosyl ester), quercetin 3-glucoside, quercetin 3-rutinoside, p-coumaric acid, epicatechin, methyl ellagic acid derivatives (e.g., methyl ellagic acetyl pentose), and citric acid derivatives also contributed significantly to the antiproliferative activity of the berry extracts. This approach enabled the identification of new bioactive components in BR fruits and demonstrates the utility of the method for assessing chemopreventive compounds in foods and food products.