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Synthesis and anti-inflammatory activities of 4H-chromene and chromeno[2,3-b]pyridine derivatives
Abstract
Several derivatives of 4H-chromene and chromeno[2,3-b]pyridine were efficiently prepared under microwave irradiation in a one-pot reaction, and their anti-inflammatory activities were evaluated. Six synthetic products (1b, 1c, 1h, 2d, 2j, and 2l) exhibited more powerfully inhibited the production of tumor necrosis factor-α-induced nitric oxide (NO) than quercetin and exhibited comparable cell viability in both human and porcine chondrocytes. In particular, 2d at dosages of 10 and 20 mg/kg had a very potent anti-inflammatory effect by suppressing the formation of carrageenan-induced rat paw edema and prostaglandin E2. The results herein suggest that these compounds may have potential as structural templates in the design and development of new anti-inflammatory drugs.
... Thus, condensed heterocyclic systems with a pyridine moiety in the structure occur in many commercially available drugs with different mechanisms of biological activity ( Figure 1). In addition, fused pyridine-based heterocycles have been identified as potent antimicrobial [6,7], anticancer [8,9], antichagasic [10], antioxidant [11,12], and antiinflammatory agents [13,14]. Furthermore, some fused pyridine derivatives were found to be inhibitors of glycogen synthase kinase-3 (GSK-3) [15], CDK5 protein kinase [16], anti-inflammatory agents [13,14]. ...
... In addition, fused pyridine-based heterocycles have been identified as potent antimicrobial [6,7], anticancer [8,9], antichagasic [10], antioxidant [11,12], and antiinflammatory agents [13,14]. Furthermore, some fused pyridine derivatives were found to be inhibitors of glycogen synthase kinase-3 (GSK-3) [15], CDK5 protein kinase [16], anti-inflammatory agents [13,14]. Furthermore, some fused pyridine derivatives were found to be inhibitors of glycogen synthase kinase-3 (GSK-3) [15], CDK5 protein kinase [16], tyrosyl-tRNA synthetase [17], cdc2-like kinase 1 (CLK1) [18], and tumor necrosis factor-α (TNF-α) [19]. ...
... The mentioned carbonyl compounds with an unsaturated chain are also effective reagents in other pericyclic reactions, especially the Diels-Alder reaction with dienophiles in constructing different polycyclic systems [26][27][28]. anti-inflammatory agents [13,14]. Furthermore, some fused pyridine derivatives were found to be inhibitors of glycogen synthase kinase-3 (GSK-3) [15], CDK5 protein kinase [16], tyrosyl-tRNA synthetase [17], cdc2-like kinase 1 (CLK1) [18], and tumor necrosis factor-α (TNF-α) [19]. ...
A series of 5-methyl-7-phenyl-3H-thiazolo[4,5-b]pyridin-2-ones has been designed, synthesized, and characterized by spectral data. Target compounds were screened for their antimicrobial activity against some pathogenic bacteria and fungi, and most of them showed moderate activity, especially compound 3g, which displayed the potent inhibitory effect against Pseudomonas aeruginosa and Escherichia coli with MIC value of 0.21 μM. The active thiazolopyridine derivatives 3c, 3f, and 3g were screened for their cytotoxicity effects on HaCat, Balb/c 3T3 cells using MTT assay, which revealed promising results. In silico assessment for compounds 3c, 3f, and 3g also revealed suitable drug-like parameters and ADME properties. The binding interactions of the most active compound 3g were performed through molecular docking against MurD and DNA gyrase, with binding energies and an inhibitory constant compared to the reference drug ciprofloxacin. The tested thiazolo[4,5-b]pyridines constitute an exciting background for the further development of new synthetic antimicrobial agents.
... Their ease of delivery and ability to be finely tuned for specific targets make them an attractive option for drug development. This study examined a novel small-molecule drug, 2-amino-4-(3,4,5-trimethoxyphe nyl)-4H-benzo[h]chromene-3-carbonitrile (CN7:1h), which is a pyridine-based derivative with potential anti-catabolic effects in an in vitro interleukin-1β (IL-1β)-induced OA model [21]. ...
... Note, however, that those interventions do not address the underlying pathology and may even exacerbate cartilage breakdown over time. In the current study, we focused on a novel small molecule synthesised by Lee et al. [21]. Many small-molecule drug compounds modulate key biochemical pathways. ...
Osteoarthritis (OA) is a degenerative joint disease with a complex aetiology, which includes inflammation, cellular growth dysregulation and extracellular matrix (ECM) degradation. This study investigated the therapeutic potential of a small‐molecule compound, 2‐amino‐4‐(3,4,5‐trimethoxyphenyl)‐4H‐benzo[h]chromene‐3‐carbonitrile (CN7:1h) in modulating these critical biochemical pathways in OA. Cellular models and rat models of OA were used to explore the impact of CN7:1h on the nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) and mechanistic target of rapamycin (mTOR) signalling pathways. Parameters such as autophagy, apoptosis and ECM preservation were evaluated. CN7:1h demonstrated a non‐cytotoxic profile at a concentration as high as 140 μM as confirmed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. At a concentration of 5 μM, CN7:1h was shown to inhibit the activation of NF‐κB and mTOR pathways. CN7:1h was also shown to promote autophagy and reduce apoptosis in cellular models. In rat models, CN7:1h facilitated cartilage repair and demonstrating the therapeutic efficacy of this compound. In conclusion, CN7:1h is a promising bioactive compound for the modulation of key biochemical pathways with therapeutic benefits in degenerative conditions, such as OA. Its high bioavailability and lack of cytotoxicity make CN7:1h an excellent candidate for further research aimed at clinical applications.
... Indeed, imidazopyridine is a biologically active compound and exhibits a wide range of biological activities such as antibacterial, antifungal, antiviral, antitumor, and anti-inflammatory activities [31][32][33][34][35] . Other than this, the naturally occurring small pharmacophore 2 H -chromene and its derivatives are also known to possess a large spectrum of activities such as antiallergic, antitumor, antiviral, antioxidant, anti-inflammatory, antibacterial, and anticancer [36][37][38][39][40][41][42][43] . The high lipophilicity of 2 Hchromene derivatives allows a better cell permeability across the bacterial cell membrane [44] . ...
... Thereafter plates were incubated for 24h at 37 ˚C to the estimation of the zone of inhibition. Moreover, MIC assay was assessed previously reported[53] , 96-well plate with various concentrations at 20 0,10 0,75,50,40,36,32,28,24,20,16,12,8,4 and 2μg/ml. These plates were allowed to aliquot nutrient broth, bacterial suspension, and various concentrated test samples. ...
Antibacterial Peptide deformylase inhibitor Molecular docking study a b s t r a c t An efficient, environmentally friendly, one-pot three-component synthesis of a series of 2 H-chromene-based imidazo[1,2-a]pyridines had been designed and were synthesized. This protocol was developed by the reaction of substituted 2 H-chromene aldehydes and 2-aminopyridine in a mixture of nitroalkane and DMF under microwave irradiation at 60W, 100 °C in 15 min with the presence of FeCl 3 as the catalyst. The products were obtained in excellent yields with high functional group tolerance. All these compounds had been investigated further in vitro for evaluation of antibacterial potency by agar-well diffusion method against human pathogenic Gram-positive and Gram-negative bacteria, with the determination of minimum inhibitory concentration (MIC) values. Indeed, compound 13i strongly inhibited peptide deformy-lase (MIC = 16 μg/ml) in the Gram-negative Escherichia coli, in silico. From structure-activity relationships based on the biological and molecular docking results and the potent antibacterial activities, it could be stated that the selected synthetic compounds could be used as potent drugable antibacterial agents.
... Pyridine is a fundamental organic heterocyclic molecule and its precursor, dihydropyridine, are among the most common structural units in the pharmaceutical industry [7]. Extensively pyridine and its derivative containing drugs are mostly used as antimicrobial [8], antiviral [9], anticancer [10], antioxidant [11], antimycobacterial [12], antidiabetic, antimalarial [13], antihypertensive [14], anti-inflammatory agents [15] and anti-HIV [16]. The pyridine derivative is established in several medicinal drugs like sorafenib and in different agrochemicals like picloram, nitapyrin and pyridinenitrile. ...
In present investigation, a novel series of (E)-3-(2-morpholino-9H-pyrido[2,3-b]indol-3-yl)-1-phenylprop-2-en-1-one and its derivatives (5a-f) were synthesized by condensation reaction from the final intermediate, 2-morpholino-9H-pyrido[2,3-b]indol-3-carbaldehyde (4). The synthesis of the title compounds commenced from commercially available 21H-indol-2-amine (1) and by involving N-(1H-indol-2-yl)-acetamide (2) and 2-chloro-9H-pyrido[2,3-b]indole-3-carbaldehyde (3) as reactive intermediates. The chemical structure of synthesized compounds was characterized by IR, 1H NMR, mass spectral data and elemental analysis. The final compounds were used to screen for their antibacterial activity against various strains of bacteria.
... Chromene is the major backbone of versatile polyphenols and is abundant in tocopherols, natural alkaloids, anthocyanins, and flavonoids [2]. Certain natural and synthetic chromene derivatives have been shown to have significant biological effects such as antitumor, antivascular [3][4][5], antimicrobial [6][7][8], and antioxidant properties, TNF-α inhibitor [9][10][11], antifungal [12][13][14][15], anticoagulant, antispasmolytic, estrogenic [16][17][18], antiviral [19][20][21], antihelminthic, anticancer [21][22][23][24][25], anti-HIV [26,27], antitubercular [28][29][30], anti-inflammatory [31,32], herbicidal, analgesic, and anticonvulsant [33][34][35] activity. The good lipophilicity of the benzopyran derivatives allows them to easily pass the cell membrane [36]. ...
Utilizing microwave heating and an aqueous saturated solution of K2CO3 as a catalyst, a rapidone-pot synthesis of oxospiro[chromene-4.3-indoline] derivatives was produced in high yields. The experimental results confirmed that the saturated solution of K2CO3 gives outstanding yield to dangerous metals and strong bases during investigations into high-performance catalysts. The used catalyst is green, affordable, incredibly mild, and widely accessible. However, it generates samples, reduces the amount of byproducts, and is expected to be used in industrial-scale heterocyclic derivatives. New oxospiro[chromene-4.3-indoline] derivatives have been created from various isatin by condensing with various phenols. The biological activities results showed that when compared to erlotinib, the derivatives 3b, 4b, 5b, and 6b were the most effective analogues on A549, MCF-7, HepG-2, and HCT-116 cells, with an IC50 range of 3.32 to 11.88 µM. In A549 cells, compounds 3b, 4b, 5b, and 6b induced apoptosis, as shown by the up-regulation of Bax, the up-regulation of Bcl-2, and the stimulation of caspase-3 and -9. With IC50 value of 0.19 ± 0.09, compound3b was demonstrated to be the most effective against EGFRWT. Compounds 4b and 6b have good antibacterial activity toward Staphylococcus aureus, comparable to ciprofloxacin, and about half as much activity as ampicillin, according to the MIC value. Compound 6b’s MIC is about 25% lower than clotrimazole drug. The in silico molecular docking outcomes of compounds 3b, 4b, 5b, and 6b in the EGFR active site depicted their ability to adopt essential binding interactions compared to the reference Erlotinib. Moreover, the investigation of the physicochemical properties of the most promising dual acting antiproliferative and antimicrobial compounds 4b and 6b through the egg-boiled method illustrated acceptable lipophilicity, GIT absorption, and blood–brain barrier penetration characteristics.
... It has been acknowledged that chromone is a privileged structure for the creation and development of new drugs [17]. Chromone exhibit medicinal properties such as antibacterial [18], antifungal [19], antiinflammatory, antimalarial [20], antioxidant [21], antiviral [22] and HIV inhibitory potential [23]. Due to beneficial action and low toxicity, chromone and its derivatives show promising anti-diabetic potential [17,20]. ...
Type-2 Diabetes Mellitus (T2DM) is one of the most common metabolic disorders in the world and over the past three decades its incidence has increased drastically. α-Glucosidase inhibitors are used to control the hyperglycemic affect of T2DM. Herein, we report the synthesis, αglucosidase inhibition, structure activity relationship, pharmacokinetics and docking analysis of various novel chromone based thiosemicarbazones 3(a-r). The derivatives displayed potent activity against α-glucosidase with IC50 in range of 0.11 ± 0.01-79.37 ± 0.71 µM. Among all the synthesized compounds, 3a (IC50 = 0.17 ± 0.026 µM), 3g (IC50 = 0.11 ± 0.01 µM), 3n (IC50 =0.55 ± 0.02 µM), and 3p (IC50 = 0.43 ± 0.025 µM) displayed higher inhibitory activity as compared to the standard, acarbose. Moreover, we have developed a statistically significant 2DQSAR model (R2tr:0.9693; F: 50.4647 and Q2 LOO:0.9190), which can be used in future to further design potent thiosemicarbazones as inhibitors of α-glucosidase.
... Chromones are a distinct class of heterocycles and are secondary metabolites produced by plants (Robin et al. 2012). Chromone scaffold was found in nature as well as in synthetic compounds and exhibits a broad spectrum of biological activities including anti-viral (Anil et al. 2013), anti-microbial (Harpreet et al. 2013), anti-inflammatory (An-Rong et al. 2016), anti-convulsant (Ahmed et al. 2010), anti-oxidant (Arpad et al. 2017), anti-cancer (Bo et al. 2016), anti-tubercular (Apurba et al. 2021), and many more. Chromone moiety serves as an important structural unit in medicinal chemistry due to extensive utilization in the synthesis of various drugs with distinct pharmacological activities including cromolyn was used to treat mastocytosis (Cem et al. 2013), nedocromil was used for the prevention of asthma as an inhaled anti-inflammatory (Keenan et al. 1994), apigenin derived from plant material is used for treating cancer therapy (Huanjie et al. 2017). ...
A new series of 2-aminochromone-based N,N-di-1,2,3-triazole hybrid heterocycles were synthesized in one pot from N,N-terminal dialkyne 2-aminochromone with various organo azides by following the click strategy using classical Cu(I)-catalyzed azide-alkyne [3 + 2] annulation reaction. The synthesized compounds were well characterized by using various spectral analyses such as IR, 1H NMR, 13C NMR, and HRMS data for their structural elucidation. All newly synthesized compounds have been investigated for anti-microbial activity against Gram-positive, Gram-negative bacteria, and fungal strains and exhibited high activity against microbial growth when compared with standard anti-bacterial agents. These derivatives were tested for anti-cancer activity against HeLa cell lines and found that all compounds exhibit good activity with IC50 values ranging from 0.11 to 1.04 µM than standard curcumin (IC50 4.83 ± 0.44 µM). The molecular docking studies of the synthesized compounds with the affinity of ligands toward the target protein dual-specificity tyrosine-regulated kinase 2, DYRK2 (PDB id: 5ZTN) molecular docking were shown a better Moldock score performed compared to standard.
Graphic abstract:
Supplementary information:
The online version contains supplementary material available at 10.1007/s11696-022-02449-w.
... 24 Moreover, Chung et al reported a set of different tricyclic chromeno-pyridines as promising anti-inflammatory agents. 25 As a representative example, compound 2 exerted potent anti-inflammatory effect through reducing the formation of PGE 2 at 10-20 mg/kg dose. Furthermore, the pyridoacylsulfonamide derivative 3 was described as COX-2 inhibitor with IC 50 equal to 5.6 µM, 26 and it strongly inhibited PGE 2 (IC 50 = 0.15 µM) in a comparable potency to celecoxib (IC 50 = 0.10 µM). ...
Background and Purpose
Because of gastrointestinal irritation and kidney toxicity associated with non-steroidal anti-inflammatory drugs and the cardiovascular problems of Coxibs use, developing novel anti-inflammatory agents with reduced toxicity and improved selectivity remains a major challenge. Depending on our previous work, a novel series of pyridopyrimidinones IIIa-i has been synthesized via reaction of 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (I) and phenyldiazenyl aromatic aldehydes (IIa-i). All the new constructed compounds were fully characterized by elemental and spectral analysis.
Methods
The target compounds IIIa–i were investigated for their potential towards COX inhibition, anti-inflammatory properties using carrageenan induced edema model in rat paw, and the ulcer indices of the most active members.
Results
The ethyl pyridopyrmidinone-benzoates IIIf, IIIg and IIIh showed superior inhibitory activity of carrageenan induced edema to celecoxib. Furthermore, the pyridopyrimidinones IIId, IIIf, IIIg, and IIIi exerted improved COX-2 inhibitory activity (IC50 = 0.67–1.02 µM) comparing to celecoxib (IC50 = 1.11 µM). Moreover, the gastric ulcerogenic potential assay of compounds IIIf–h revealed their lower ulcerogenic liability than indomethacin with comparable effect to celecoxib.
Conclusion
Virtual docking investigation of the most active candidates IIId, IIIf, IIIg and IIIi in the active site of COX-2 enzyme showed that these compounds implied interaction and binding motif similar to the cocrystallized ligand bromocelecoxib.
... Carrageenan induced hind paw edema method with few modifications was applied to assess anti-inflammatory activities of the compounds (Chung et al., 2016). Thirty-five Wister rats were designated into seven equal groups randomly. ...
Five α-D-ribofuranose analogues (2, 3, 4, 5 and 6) were synthesized in good yields from 3-O-benzyl-4-C-(hydroxymethyl)-1, 2-O-isopropylidene-α-D-ribofuranose (1). The synthesized compounds were then subjected to analgesic, anti-inflammatory, antimicrobial and antioxidant assays. Compound 3 demonstrated 79.74% (P <0.001) writhing inhibition and highest reaction time of 2.55 ± 0.13 min (P <0.001) after 30 minutes of oral administration in peripheral and central analgesic assay, respectively, at 50 mg/kg dose. Compound 2 and 6 exhibited significant anti-inflammatory activity at 100 mg/kg dose with paw edema inhibition of 91.15% (P <0.001) and 95.13% (P <0.001), respectively, in 4th hour. The synthesized analogues did not show notable antioxidant and antibacterial properties. Molecular docking study revealed higher binding affinity of -8.1 kcal/mol and -8.9 kcal/mol of compound 3 towards cyclooxygenase-1 and phospholipase A2, respectively, compared to -7.7 and 7.6 kcal/mol respectively for corresponding native ligands. Compound 2 demonstrated binding affinity of -9.1 kcal/mol towards interleukin-1 receptor-associated kinase-4 compared to -8.7 kcal/mol of the native ligand. The molecular properties related to drug likeness of compounds were found to be within acceptable range. Synthesized D-ribofuranose analogues demonstrated promising analgesic and anti-inflammatory activities and further development may lead to new potent analgesic and anti-inflammatory agents.
... The classical CA inhibitors (CAIs) are the primary sulfonamides, which coordinate the zinc ion with their terminal deprotonated nitrogen atom and have been in clinical use for more than 70 years as diuretics and systemically acting antiglaucoma drugs [10]. Chromenes have attracted the interest of the scientific community due to their wide range of biological activities, such as antimicrobial [11,12], anticancer [13,14], anti-inflammatory [15,16], and CA inhibitors [17][18][19][20][21], nematicidal [22], antiallergic [23] Some sulfonamides also show antimicrobial [24,25], anticancer [26,27], antidiabetic [28], anti-inflammatory [15,29], and antitubercular [30] activities. Taking into account all of the above-mentioned, here we report the synthesis of (4-sulfamoylphenyl)-4H-chromene-2-carboxamide derivatives for its incorporation into one scaffold chromene and sulfonamide moieties. ...
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.
... The construction of chromenopyridines usually relies on domino or multicomponent reactions of salicylaldehydes 1 and excess amounts of malononitrile (or malononitrile dimer) [12][13][14][15][16][17]. We have recently shown that homophthalonitrile 2 works as a vinylogous malononitrile, annulating an isoquinoline ring. ...
An interaction of homophthalonitrile with salicylaldehydes proceeds as a novel domino reaction and results in the formation of nineteen 12H-chromeno[2,3-c]isoquinoline-5-amine derivatives. Four new bonds and two cycles are forged in a single synthetic operation, employing cheap and eco-friendly ammonium formate, acting both as a catalyst and a reducing agent. The in vitro cytotoxicity tests revealed antiproliferative activities against five human tumor cell lines, including the cisplatin-resistant ovarian carcinoma one (A2780cp8), with inhibitory potency data (IC50) in the low micromolar range in most cases. Molecular docking calculations and fluorescence quenching studies revealed possible binding properties with DNA of the active compounds.
A synthetic strategy involving salicylaldehyde, 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF), and pyrrole has been developed to construct novel pyrrole-4 H -chromene-embedded vinyl sulfonyl fluoride derivatives with exclusive regioselectivity.
The chemistry of heterocyclic compounds has traditionally been and remains a bright area of chemical science in Russia. This is due to the fact that many heterocycles find the widest application. These compounds are the key structural fragments of most drugs, plant protection agents. Many natural compounds are also derivatives of heterocycles. At present, more than half of the hundreds of millions of known chemical compounds are heterocycles. This collective review is devoted to the achievements of Russian chemists in this field over the last 15–20 years. The review presents the achievements of leading heterocyclists representing both RAS institutes and university science. It is worth noting the wide scope of the review, both in terms of the geography of author teams, covering the whole of our large country, and in terms of the diversity of research areas. Practically all major types of heterocycles are represented in the review. The special attention is focused on the practical applications of heterocycles in the design of new drugs and biologically active compounds, high-energy molecules, materials for organic electronics and photovoltaics, new ligands for coordination chemistry, and many other rapidly developing areas. These practical advances would not be possible without the development of new fundamental transformations in heterocyclic chemistry.
Bibliography — 2237 references.
A highly efficient and environmentally friendly method for the synthesis of 2‐amino‐4 H ‐chromene‐3‐carbonitrile (ACC) derivatives has been successfully established. This innovative, solvent‐free approach involves a tandem three‐component and one‐pot reaction utilizing arylaldehyde, dicyanomethane, and dimedone/cyclohexane‐1,3‐dione, catalyzed by 2‐aminopyrazine under the mortar‐pestle grinding technique. Key attributes of this synthetic strategy include its simplicity, high efficiency, cost‐effectiveness, absence of column chromatography, shorter reaction times (18–40 min), and consistently high yields (89%–96%). Furthermore, computational studies have been conducted against the 4RHT protein using the synthesized compounds.
An efficient and environmentally benign In(OTf)3 catalysed multicomponent approach for the synthesis of spiroannulated pyridopyrimidines, chromenopyridines, indenopyridines and quinolines has been presented for the first time. The current approach uses an indium triflate as a catalyst in a one-pot four-component reaction of isatin, malononitrile, 1,3-Diketone, and 4-ethylaniline in ethyl alcohol. The current protocol presents multiple advantages that including operational simplicity with easy workup, moderate reaction conditions, shorter reaction times (25–40 min), excellent yields (85–96%) with superior atom economy, green and environmentally benign reaction conditions due to the use of recyclable and reusable non-toxic metal catalyst.
Graphical abstract
The Trimethoxyphenyl (TMP) group serves as a pharmacophore in numerous potent agents exhibiting diverse bioactivity effects. This moiety is prominently present in the molecular structures of various research studies, demonstrating remarkable multi-activity or specific targeting, surpassing the activity of other derivatives at comparable concentrations. The compounds containing the TMP group have displayed notable anti-cancer effects by effectively inhibiting tubulin, heat shock protein 90 (Hsp90), thioredoxin reductase (TrxR), histone lysine-specific demethylase 1 (HLSD1), activin receptor-like kinase-2 (ALK2), P-glycoprotein (P-gp), and platelet-derived growth factor receptor β. Furthermore, select TMP-bearing compounds have shown promising anti-fungal and anti-bacterial properties, including activities against Helicobacter pylori and Mycobacterium tuberculosis. Additionally, there have been reports on the antiviral activity of TMP-based compounds, which hold potential against viruses such as the acquired immunodeficiency syndrome (AIDS) virus, hepatitis C virus, and influenza virus. Compounds containing the TMP pharmacophore have also demonstrated significant efficacy against Leishmania, Malaria, and Trypanosoma, indicating their potential as anti-parasitic agents. Furthermore, these compounds have been associated with anti-inflammatory, anti-Alzheimer, anti-depressant, and anti-migraine properties, thereby expanding their therapeutic scope. This paper presents a comprehensive and categorized review of these diverse properties of TMP-bearing compounds, shedding light on their potential as valuable agents across a wide range of biomedical applications.
A simple, efficient, and eco-friendly process for the Knoevenagel condensation between various aromatic aldehydes and active methylene compounds and the synthesis of 2-amino-4H-chromene derivatives via a multi-component reaction of various aromatic aldehydes, malononitrile, and resorcinol catalyzed by mono-ammonium phosphate fertilizer (MAP) modified by cadmium chloride (CdCl2) is described. This synthesis procedure is considered an attractive method due to its excellent yields, short reaction time, green conditions, cost-effectiveness, use of a non-toxic solvent, non-chromatographic purification of products, and recyclability of the catalyst.
A simple, efficient, and ecofriendly process is proposed to synthesize 2-amino-4H-chromene and 2-(4-chlorobenzylidene) malononitrile derivatives via the application of cadmium pyrophosphate (Cd2P2O7) as catalyst prepared from the modification of mono-ammonium phosphate fertilizer (MAP) by adding cadmium chloride (CdCl2). The products were obtained with good yields in a short reaction time.
In Search of new antibacterial, antifungal agents with improved potency, herein we report the synthesis of a series of new substituted 2-(4-fluorophenyl)-3-((1-phenyl-1H-1,2,3-triazol-4-yl)methoxy)-4H-chromen-4-one derivatives (6a‐q), starting from acetophenone. All the synthesized compounds have been screened for in vitro antibacterial and antifungal activity by using the agar well diffusion method. Among fifteen synthesized compounds, four chromone derivatives i.e. (6a-b), (6h), and (6i) have shown proficient antimicrobial activities. Compound (6a) showed powerful inhibitory activity against all bacterial pathogens but it was not that effective against fungal pathogens on the other hand compound (6b) showed satisfactory activity against fungal pathogens as well. The activity of compounds (6h) and (6i) against S. aureus was remarkable. Other compounds were found active against a few pathogens but activity was good. The compound (6b) was found very effective in inhibiting the growth of S. aureus ATCC 6538 at a low concentration with MIC 190 µg/ml.
A new pseudopolymeric nanomagnetic catalyst containing urea linkers, namely Fe3O4@SiO2@[(CH2)3–urea–(CH2)2–O–(CH2)]2, was synthesized. The mentioned nanomagnetic catalyst was characterized by using several methods including Fourier transform infrared spectroscopy, thermogravimetric/differential thermogravimetric analysis, vibrating sample magnetometer analysis, scanning electron microscopy, transmission electron microscopy, and energy-dispersive X‐ray analysis. In this research, we examined the catalytic usage of Fe3O4@SiO2@[(CH2)3–urea–(CH2)2–O–(CH2)]2 for the preparation of a wide range of 2‐amino‐3‐cyano and 2‐hydroxy‐3‐cyanopyridine derivatives bearing thiophene or furan moieties. All desired hybrid pyridines were synthesized in short reaction times with high yields. The crucial finding is that the catalyst was very efficient, stable, and easy retrieve. In addition, a vinylogous anomeric-based oxidation pathway is suggested as a mechanism for the preparation of target molecules.
Graphical abstract
In recent years, the fundamental variety and biological influence of pyridine and its derivatives make them fascinating aims for preparation. These versatile compounds can be found in several bioactive natural products, drugs, functional materials and have been known as important chemical and pharmaceutical agents. As a result, the synthesis of pyridines remains an attractive subject to industrial and synthetic chemists. Based on the aforementioned properties, in this chapter, the recent advances in the catalytic synthesis of pyridine and its derivatives are collected. Several heterogeneous and homogeneous catalytic methods such as acidic and basic catalysts, nanocatalysis, ionic liquids, and molten salts, supported catalysts, transition metal catalysis, organocatalysts, I2, etc. have been employed for the synthesis of pyridines. Furthermore, these interesting compounds were constructed by numerous protocols such as metal-free catalysis, classical heating, sonication, and microwave irradiation by using solvents or solvent-free conditions. Also, this chapter highlights regioselectivity, isolated yields, and reaction conditions for the catalytic synthesis of pyridine derivatives.
5H-Chromeno[2,3-b]pyridine derivatives are a series of the most important compounds of chromenes with industrial, biological, and medicinal properties. These compounds are known as the privileged medicinal scaffold and can be synthesized by different methods such as multicomponent reactions (MCRs), Multicomponent coupling reactions (MCCRs), pot, atom, and step economy (PASE). In this review article, we have focused on the significant reactions for the syntheses and applications of 5H-chromeno[2,3-b] pyridines, including two-component reactions, three-component reactions, fourcomponent reactions, and multi-step reactions. This review is expected to serve as a useful conceptual overview and inspire the next generation to develop the different strategies for the preparation of 5HChromeno[2,3-b] pyridine derivatives.
By employing the naturally-originated molecule of creatine, Fe3O4@SiO2-creatine as an environmentally benign magnetic organometallic nanobiocatalyst was successfully prepared via a convenient and green route. Then to acquire an inclusive comprehension of different properties of the catalyst, it was studied by various characterization techniques such as FT‐IR, FE-SEM, TEM, EDX, XRD, and VSM analyses. It was found that the size distribution of nanoparticles was an average diameter size of 70 nm. To examine the catalytic activity, it was applied in sequential knoevenagel condensation-Michael addition room temperature reaction of dimedone, malononitrile, and different substituted aromatic aldehydes to produce a variety of 2-amino-tetrahydro-4H-chromene-3-carbonitrile derivatives in a single step. Among the multiple outstanding advantages that can be mentioned for this work, some of the most noticeable ones include: affording the products in short reaction times with high yields, operating the reaction at ambient conditions and ease of catalyst separation.
Background:
The inflammatory response is a common feature of many pathological conditions, and there is urgent necessity for new substances that minimize the harmful effects of inflammation. Chromenes represent a class of compounds with multiple pharmacological actions that have already been described and may be potential candidates for studies of therapeutic action.
Objective:
This study aimed to test novel 4-aryl-4H-chromene-derived molecules in an in vitro model of inflammation using lipopolysaccharide (LPS)-induced Raw 264.7 cells.
Methods:
Seven compounds derived from 4-aryl-4H-chromene were tested on Raw 264.7 cells to evaluate their cytotoxic effects. Next, the effect of the selected compounds on the pro-inflammatory mediators (TNF-α, MCP-1, IL-6) and on the anti-inflammatory mediators (IL-10, and IL-13) was analyzed, and finally, the effect of the compounds on macrophage apoptosis and expression of surface receptors (TLR-4 and Mannose) was evaluated.
Results:
The results of this study demonstrated that changes in the molecular structure of 4-aryl-4H-chromene altered its cytotoxic profile. Therefore, derivatives that showed safe results were selected for further analyses (named compounds: 4, 5, and 6). In these experiments, the compounds were able to decrease NO levels and production of MCP-1, IL-6, IL-10 and IL-13. Furthermore, these derivatives were effective in reducing macrophage apoptosis and the expression of surface receptors, as toll-like receptor 4 (TLR-4/CD284). Moreover, compounds 5 and 6 also were effective in increasing mannose receptor (CD206) expression.
Conclusion:
The results indicate, for the first time to our knowledge, that the anti-inflammatory effect produced by chromenes is linked to macrophage repolarization (M1 to M2).
Neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's disease (PD) usually starts gradually and progressively worsens, and are recognized as one of the leading causes of mortality and disability worldwide. Presently, all the available drugs for AD and PD are only for symptomatic relief, and are not capable of preventing and curing the disease. Chromone is a privileged structure for designing of novel drug agents with pharmacological potential, specifically in the field of AD and PD. The present review is focused on the significance of chromones as novel drug agents for the treatment of AD and PD. Chromone based acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, β‐Secretase‐1, inhibitors are discussed. As AD belongs to one of the most complex and multifactorial disorders, therefore, the multi‐target drugs are urgently required. However, there has been a substantial research effort in designing multi‐target drug agents. Therefore, in this review, chromone based multi‐target inhibitors are also discussed. Furthermore, future directions for designing and developing potent chromone based drugs are reported.
Chromene is commonly found in nature and is considered one of the most frequently used scaffolds in heterocyclic chemistry for the designing of chemical probes for therapeutic and diagnostic purposes. The chromene nucleus comprises an oxine ring fused with a phenyl ring. Owing to existing several useful biological applications of chromenes have generated wide interest among chemists to synthesize its derivatives frequently. Here, in this review, we have compiled and analysed various recently reported synthetic strategies of chromene and its derivatives through numerous approaches such as microwave-assisted, catalyst based, green solvents, solvent-free conditions, etc. along with their biological applications such as anticancer, antimicrobial, anti-proliferative, anti-inflammatory, AChE inhibition, antiviral, and antioxidant activities.
Magnetic Fe3O4‐based hydrotalcites were used as bifunctional catalysts for the microwave‐assisted solvent‐free synthesis of 4H‐chromene derivatives by a three‐component reaction from (hetero)aromatic aldehydes, malononitrile, and naphthol derivatives. Structures of 4H‐chromenes 4 d and 4 g were studied and confirmed by single‐crystal X‐ray diffraction analysis. The heterogeneous catalysts were synthesized by the co‐precipitation method incorporating divalent metal cations such as Ni²⁺ or Co²⁺ in LDH−Mg. This multicomponent protocol allows the synthesis of diverse 4H‐chromenes in 88–95 % yields, reduced reaction time, high atom economy, broad substrate scope, and operational simplicity. The reusability of the catalyst up to five recycles without appreciable loss of its catalytic activity, make the present protocol sustainable and advantageous compared to conventional methods.
Coumarin derivatives occur widely in nature and have been a part of both traditional and modern advancements in synthesis and application. To date, thousands of coumarin derivatives have been synthesized in labs or isolated from plant and marine life. These are essentially 2-pyrone core fused with a benzene ring and belong to the family of aromatic oxygen heterocycles. Coumarin in conjugation with various other heterocyclic systems has provided a robust framework in tuning the properties associated with the parent structure. The frequency of reports increased for these biheterocyclic systems from the mid of the twentieth century. Biheterocyclic coumarins also attracted many organic, and pharmaceutical chemists as these systems serve as useful synthetic intermediates in the synthesis of analogs of existing drugs. Its application in the design of effective organocatalysts and chemosensors further extended its versatility. Coumarin biheterocyclic core is utilized in the rational design and tuning complex molecular entities in molecular recognition, analytical and material chemistry. This review will highlight the advancements in the synthesis and applications of coumarin-linked nitrogen, oxygen, and sulfur heterocycles. It will also engage an account of forming five-, six-, and seven-membered heterocyclic rings linked to coumarin core. Critical physicochemical properties coupled with its application will make this review handy for synthetic chemists and drug discovery labs. A comprehensive spectrum of literature in this review will facilitate further development in biheterocycles with promising applications in the future.
Among the various other organic compounds, the compounds having heterocyclic core are extensively circulated in nature and are often crucial for life. The concerned heterocyle may or may not be aromatic. They often show a variety of physiological, industrial and also theoretical significance. Quinoline derivatives are very popular anti‐biotics and benzopyran or chromenes is another important heterocyclic moiety found widely in naturally occurring plant products like fruits and vegetables. However, when chromene and quinoline are present in a molecule in fused form, a subclass of very important bio‐active chromene‐fused quinoline heterocycles is formed. This review covers recent reports on transition metal‐free synthesis of chromeno‐quinoline derivatives in short and hassle‐free reaction protocols.
The Lewis acids of the sort ZnX2 (X = Cl, Br, OTf & I) are rather simple and mild yet proves its efficiency in enabling wide range of synthetic transformations in organic synthesis. Specifically, important heterocyclic molecules such as acridines, spiro-isoxazole-5-one-tetrahydro-quinolines, imidazole derivatives, cyclopenta[b]pyrroles, chromenes, furans, and benzofurans have been accomplished by using ZnX2. The foremost benefits of ZnX2 are its cost-effectiveness and low toxicity. The ZnX2 acts as an aid for most of the weak nucleophiles to react with broad range electrophiles such as carbonyl, imine, cyano, and acetylene groups by coordinating with heteroatom thereby increases its electrophilicity. Besides, ZnX2 also assists most reactions by enabling reaction in short time by using mild condition. This review encompassed with some potent methodologies that have been developed towards organic synthesis in the past five years by employing zinc-based Lewis acid as a catalyst/reagent.
A new, one-pot, efficient, and four-component condensation of 2-hydroxynaphthalene-1,4-dione, benzene-1,2-diamine, arylaldehydes and (phenylsulfonyl)acetonitrile in the presence of a reusable basic ionic liquid, 2-hydroxyethylammonium formate, as catalyst for the synthesis of novel 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives under solvent-free conditions at 80 °C was described. A simple reaction and work-up procedure for the synthesis of new un-known compounds using a green and reusable ionic liquid as catalyst under solvent-free and thermal conditions was reported. The easy preparation of ionic liquid was superiority of the mentioned basic ionic liquid. This protocol has various advantages such as short reaction times, excellent yields, no column chromatography, and green environmentally safe media.
Graphical abstract
A variety of new pentacyclic dichromenopyridines have been synthesized from 2-amino chromone and O-propargyloxy salicilaldehydes through intramolecular Povarov reaction using CuI/Cu(OSO2CF3)2 as a Lewis acid catalyst. The dichromenopyridines synthesis involve two sequential steps, insitu N-heteryl aldimine formation and an intramolecular Aza Diels-Alder[4 + 2] cycloaddition. Furthermore the key intermediate, terminal alkyne tethered Schiff bases subjected to Cu(I) mediated click [3 + 2] cycloaddition with thiazole appended azide to afford imine linked chromone-1,2,3-triazole -thiazole tri heterocyclic molecular hybrids.
A practical 1,3-dipolar [3+2] cycloaddition of N-2,2,2-trifluoroethylisatin ketimines and (Z)-4-((chromone-3-yl)methylene)oxazolones under phase-transfer catalysis is described. Using tetrabutylammonium bromide as a catalyst, the cycloaddition allows rapid assembly of a series of bispiro heterocycles merging five pharmacophores, the trifluoromethyl group, oxazolone, pyrrolidine, oxindole, and chromone motifs, with moderate to excellent yields and excellent diastereoselectivities. Studies on the reaction kinetics show the high efficiency of the phase-transfer catalytic strategy.
As a part of green chemistry advancements, particularly in the field of synthetic organic chemistry, the concept of self-catalytic synthesis has recently emerged. Accordingly, the last decade has seen an ongoing development in designing organic synthetic protocols without the aid of any added catalysts. Catalyst-free synthetic processes have manifolds of benefits so as to get rid of toxicity and wastes associated with using these catalysts. Hence, designing of catalyst-free synthetic processes is a step forward toward safe, cost-effective, waste-free, simple, and sustainable environment. The present book chapter focuses on the recent update in the area of catalyst-free syntheses of heterocycles of biological interest at room temperature, reported since 2017.
The review summarizes and systematizes data on the methods for the preparation of chromeno[2,3- b ]pyridines. Both multicomponent and pseudo-multicomponent synthetic approaches and one-pot transformations based on the reactions of carbonyl compounds, malononitrile or its derivatives, and CH-acids are considered. Examples of the use of various catalysts, microwave and ultrasonic radiation, as well as electric current for the implementation of multicomponent transformations of this type are given. Characteristic features of the course and mechanisms of reactions are discussed. Data on the biological activity of the obtained compounds and on other fields of application of such heterocyclic systems are presented.
The bibliography includes 109 references.
A new series of 1-(6-amino-3,5-dicyano-4-(substituted)pyridin-2-yl)-4-methylthiosemicarbazide derivatives 4(a–i) was achieved by the reaction of malononitrile and 4-methyl-3-thiosemicarbazide with various aldehydes. All the newly designed compounds were structurally established by various analytical methods (IR, ¹H, ¹³C NMR, and HRMS). Further, all the entitled derivatives were evaluated for their potential antioxidant activity by DPPH radical method in which standard, ascorbic acid, was used for comparison and results revealed that the derivatives, 4a and 4i exhibited the highest antioxidant effect.
An efficient one-pot synthesis of 2-[3-(2-amino-4-oxo-4Hchromen-3-yl)-1-arylallylidene]malononitriles as intermediates and 2-aryl-5H-chromeno[2,3-b]pyridin-5-ones as final products comprises Et3N-catalyzed condensation of alkylidenemalononitriles, 3-formylchromones and hydroxylamine hydrochloride. The transformation involves stages of 1,4-nucleophilic addition, phenolate–nitrile coupling and Mannich-type heterocyclization reactions.
Infections by flaviviruses, such as Dengue, West Nile, Yellow Fever and Zika viruses, represent a growing risk for global health. There are vaccines only for few flaviviruses while no effective treatments are available. Flaviviruses share epidemiological, structural, and ecologic features and often different viruses can co‐infect the same host. Therefore, the identification of broad‐spectrum inhibitors is highly desirable either for known flaviviruses or for viruses that likely will emerge in the future.
Strategies targeting both virus and host factors have been pursued to identify broad‐spectrum antiflaviviral agents. In this review, we describe the most promising and best characterized targets and their relative broad‐spectrum inhibitors, identified by drug repurposing/libraries screenings and by focused medicinal chemistry campaigns. Finally, we discuss about future strategies to identify new broad‐spectrum antiflavivirus agents.
Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared from hydroquinone and resorcinol through their reaction with ethyl acetoacetate. These hydroxy coumarins were then converted into corresponding alkoxy derivatives by reaction with alkyl halides. The yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55−95%. Oxidation of these compounds by selenium dioxide under conventional and microwave-assisted heating conditions produced corresponding 4-formyl compounds 5b–h and 6b–h with yields of 40−67% and 90−93%, respectively. Several 6- and 7-alkoxy-4-methylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h are novel compounds.
The magnetic biocompatible rod‐like ZnS/CuFe2O4/agar organometallic hybrid catalyst was designed and prepared based on a natural macromolecule (agar) through a green and convenient method using inexpensive, nontoxic, and easily available substances. Then, the as‐prepared catalyst was characterized by several techniques such as Fourier transform‐infrared spectroscopy, energy‐dispersive X‐ray analysis, scanning electron microscopy image, transmission electron microscopy, vibrating sample magnetometry curve, X‐ray diffraction pattern, and thermogravimetric analysis. Eventually, the catalytic application of the ZnS/CuFe2O4/agar nanobiocomposite was assessed in sequential Knoevenagel condensation–Michael addition reaction of dimedone, malononitrile, and different substituted aromatic aldehydes for the synthesis of 2‐amino‐tetrahydro‐4H‐chromene‐3‐carbonitrile derivatives. Some notable strengths of this environmentally benign catalyst include simplicity of catalyst preparation and separation, affording desired products with satisfactory yields (81%–97%) in very short reaction times (3–18 min), and with no need for complicated work‐up processes. Experimental tests showed that the catalyst can be successfully reused after five sequential runs without significant reduction in its catalytic efficiency. The biocompatible rod‐like ZnS/CuFe2O4/agar organometallic catalyst prepared based on agar, conveniently. It was characterized by FTIR, EDX, SEM, TEM, TGA, VSM and XRD analyses. Investigation of its catalytic application in the synthesis of 2‐amino‐tetrahydro‐4H‐chromene‐3‐carbonitrile derivatives showed that desired products produced with high yields (81%–97%) in very short reaction times (3–18 min). The catalyst can be reused after five sequential runs without significant reduction in its catalytic efficiency.
A simple and efficient method for the synthesis of novel 4‐hydroxy‐4H‐chromene‐pyrazoles and 4‐hydroxy‐4H‐chromene‐barbiturates was developed from the reaction of 2‐ethoxy‐2H‐chromene chalcones with pyrazolin‐5‐one and barbituric acid catalyzed by l‐proline in water. The developed protocol is applicable for the construction of biologically important 4H‐chromenes from easily accessible chalcones having various substituents. This reaction proceeds through Aldol condensation, Michael addition and hydrolysis reactions followed by the elimination of ethoxy group. This methodology offers cleaner conversion, a shorter reaction time and high yields. For the first time, we report the synthesis of novel 4‐hydroxy‐4H‐chromenes from 2‐ethoxy‐2H‐chromene chalcones and pyrazolin‐5‐one/barbituric acid using l‐proline (72–86 % yield in 6 h). Water was used as the solvent for all the compounds it represents a green synthetic protocol.
An efficient basic alumina supported continuous flow method was developed for the synthesis of various chromene derivatives by one-pot three component condensation of arylaldehydes, malononitrile and dimidone using basic alumina as solid supported catalyst under continuous flow. This protocol offer various advantages such as mild reaction condition, simple work-up procedure, avoids the usage of strong acid catalysts, re-usability of catalyst, and produces higher yields in shorter reaction time with high selectivity. Chromene derivatives were characterized by different spectral analysis such as IR, ¹HNMR, ¹³CNMR, mass spectrometry and elemental analysis.
Chromone derivatives possess a spectrum of biological activities. Chromone has been recognized as a privileged structure for new drug invention and development. Substitution pattern of chromone scaffold determines different type of biological activities. The type, number and position of substituents connected to the chromone core play a vital role in determining pharmacological activities. In the present review, we have discussed new chromone derivatives as anticancer, anti-diabetic, antimicrobial, anti-inflammatory, antioxidant and as anti-Alzheimer agents. This review deals with the chromone derivatives prepared by combining chromone molecule with various natural and synthetic pharmacophores and pharmacological activities presented by them. The main aim is to highlight the diversified pharmacological activities exhibited by chromone hybrid molecules during the last eight to ten years.
A series of 2-amino-7-hydroxy-4H-chromene-3-carbonitriles 4a-l were synthesized through three-component reaction using sodium car-bonate as a catalyst. The reaction was carried out in 96% ethanol-water medium (1:20 ratio in volume). Propargyl ether compounds 5a-l of these chromene-3-carbonitriles were successfully synthesized from corresponding hydroxyl chromene derivatives by reaction with propargyl bromide. Two different procedures were applied in this process: the procedure that used potassium carbonate in dried acet-one and the procedure that used sodium hydride in dried DMF. The latter gave the ethers 5a-l in higher yields. The single-crystal X-ray structure of propargyl ether 5g has been recorded. GRAPHICAL ABSTRACT ARTICLE HISTORY
B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the tw studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.
Current therapies for asthma and allergy are relatively safe and effective at controlling symptoms but do not change the chronic course of disease. There is no established method to prevent asthma and allergy, and major unmet needs in this area include the better control of the severe forms of these diseases and the developments of curative therapies. Two major therapeutic strategies for asthma and allergy are currently being developed, and I here discuss the advances and challenges for future therapeutic development in these two areas. The first approach, allergen-specific immunotherapy, aims to induce specific immune tolerance and has a long-term disease-modifying effect. The second approach is the use of biological immune response modifiers to decrease pathological immune responses. Combination strategies using both of these approaches may also provide a route for addressing the unmet clinical needs in allergic diseases.
Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3β inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3β targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3β inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3β, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3β activity and prevented GSK3β-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3β abolished the effects of TDZD-8. Hence, inhibition of GSK3β ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.
The anti-ulcerogenic and anti-oxidant effects of various flavonoids have been frequently reported. We investigated the cytoprotective properties of quercetin, a natural flavone, in gastric mucosal injury induced by 50% ethanol, since in this experimental model the pathogenesis of the lesions has been related with production of reactive oxygen species. The involvement of neutrophil infiltration and the capacity of this flavonoid to restrain the oxidative process produced in the gastric tissue after ethanol administration were also investigated. Oral pretreatment with the highest dose of quercetin (200 mg/kg), 120 min before absolute ethanol was the most effective anti-ulcer treatment. Thiobarbituric acid reactive substances in the gastric mucosa, an index of lipid peroxidation, were increased by ethanol injury, but the increase was inhibited by the administration of 200 mg/kg of quercetin. This dose also induced a significant enhancement in the levels of mucosal non-protein SH compounds (important anti-oxidant agents) and in glutathione peroxidase activity. Exposure of the gastric mucosa to 50% ethanol induced a significant increase in myeloperoxidase activity, an index of neutrophil infiltration. Flowever, quercetin was not able to modify the increase in enzymatic activity generated by the necrotizing agent. The activity of superoxide dismutase enzyme involved in several antioxidant processes was also not significantly modified after quercetin treatment.
These results suggest that the anti-ulcer activity of quercetin in this experimental model could be partly explained by the inhibition of lipid peroxidation, through decrease of reactive oxygen metabolites. However, the inhibition of neutrophil infiltration or the increase of superoxide dismutase activity does not appear to be involved in gastroprotective effect of this flavonoid.
Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity.
Accumulation of advanced glycation end products (AGEs) in joints contributes to the pathogenesis of cartilage damage in osteoarthritis (OA). We aim to explore the potential chondroprotective effects of resveratrol on AGEs-stimulated porcine chondrocytes and cartilage explants.
Chondrocytes were isolated from pig joints. Activation of the IκB kinase (IKK)-IκBα-nuclear factor-kappaB (NF-κB) and c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK)-activator protein-1 (AP-1) pathways was assessed by electrophoretic mobility shift assay (EMSA), Western blot and transfection assay. The levels of inducible nitric oxide synthase (iNOS)-NO and cyclooxygenase-2 (COX-2)-prostaglandin E2 (PGE2) were measured by Western blot, Griess reaction or ELISA. The expression and enzyme activity of matrix metalloproteinase-13 (MMP-13) were determined by real time RT/PCR and gelatin zymography, respectively.
We show that AGEs-induced expression of iNOS and COX-2 and production of NO and PGE2 were suppressed by resveratrol. Such effects of resveratrol were likely mediated through inhibiting IKK-IκBα-NF-κB and JNK/ERK-AP-1 signaling pathways induced by AGEs. By targeting these critical signaling pathways, resveratrol decreased AGEs-stimulated expression and activity of MMP-13 and prevented AGEs-mediated destruction of collagen II. Histochemistry analysis further confirms that resveratrol could prevent AGEs-induced degradation of proteoglycan and aggrecan in cartilage explants.
The present study reveals not only the effects and mechanisms regarding how resveratrol may protect cartilage from AGEs-mediated damage but also the potential therapeutic benefit of resveratrol in the treatment of OA.
LY290181, 2-amino-4-(3-pyridyl)-4H-naphtho(1,2-b)pyran-3-carbonitrile, is a potent antiproliferative compound that blocks cells in the G2/M phase of the cell cycle by an apparent action on microtubules. In the present work we found that LY290181 bound to tubulin
with high affinity (1 mol of LY290181 per mol of tubulin dimer; Ka, 3.8 × 105 M−1) and that it did not appear to bind at the colchicine or vinblastine-binding sites. LY290181 strongly stabilized microtubule
dynamics as determined by video microscopy. It reduced the rate and extent of growing and shortening, reduced the catastrophe
frequency and increased the rescue frequency, and increased the percentage of time the microtubules spent in an attenuated
state. At the lowest effective LY290181 concentrations (0.1-0.3 μM), suppression of dynamics occurred with little reduction in polymer mass. However, at higher concentrations, LY290181 strongly
reduced the polymer mass with half-maximal inhibition at a concentration of 0.75 μM. We suggest that LY290181 may exert its antiproliferative activity by stabilizing spindle microtubule dynamics by binding
to tubulin at a novel site.
Peripheral inflammation involves an increase in cyclooxygenase-2 (COX-2)-mediated prostaglandin (PG) synthesis in the central
nervous system (CNS), which contributes to allodynia and hyperalgesia. In the present study we have determined the changes
in prostanoid tissue levels and in expression of terminal prostanoid synthases in both the CNS and inflamed peripheral tissue
during carrageenan-induced paw inflammation in the rat. Prostanoid levels were measured by liquid chromatography-mass spectrometry
and enzyme expression at the RNA level by quantitative PCR analysis during both the early (1-6 h) and late (12 and 24 h) phases
of the inflammatory response. In the paw, the early phase was associated with increases in PGE2 and thromboxane (TX)B2 levels and with a peak of COX-2 expression that preceded that of microsomal prostaglandin-E2 synthase-1 (mPGES-1). COX-2 and mPGES-1 remained elevated during the late phase, and PGE2 continued to further increase through 24 h. The cytosolic PGE2 synthase (cPGES) showed a small transient increase during the early phase, whereas mPGES-2 expression was not affected by
inflammation. In the cerebrospinal fluid, elevated levels of PGE2, 6-keto-PGF1α, PGD2, and TXB2 were detected during the early phase. PGE2 levels also increased in the spinal cord and, to a lesser extent, in the brain and remained elevated in both the cerebrospinal
fluid and the spinal cord during the late phase. The expression of mPGES-1 was strongly up-regulated in the brain and spinal
cord during inflammation, whereas no change was detected for the expression of cPGES, mPGES-2, COX-1, and terminal PGD, TX,
or PGI synthases. The results show that the carrageenan-induced edema in the paw elicits an early phase of COX-2 induction
in the CNS leading to an increase synthesis in PGD2, 6-keto-PGF1α, and TXB2 in addition to the major PGE2 response. The data also indicate that the up-regulation of mPGES-1 contributes to COX-2-mediated PGE2 production in the CNS during peripheral inflammation.
In ocular tissue, arachidonic acid is metabolized by cyclooxygenase to prostaglandins which are the most important lipid derived mediators of inflammation. Presently nonsteroidal anti-inflammatory drugs (NSAIDs) which are cyclooxygenase (COX) inhibitors are being used for the treatment of inflammatory disorders. NSAIDs used in ophthalmology, topically, are salicylic-, indole acetic-, aryl acetic-, aryl propionic- and enolic acid derivatives. NSAIDs are weak acids with pKa mostly between 3.5 and 4.5, and are poorly soluble in water. Aqueous ophthalmic solutions of NSAIDs have been made using sodium, potassium, tromethamine and lysine salts or complexing with cyclodextrins/solubilizer. Ocular penetration of NSAID demands an acidic ophthalmic solution where cyclodextrin could prevent precipitation of drug and minimize its ocular irritation potential. The incompatibility of NSAID with benzalkonium chloride is avoided by using polysorbate 80, cyclodextrins or tromethamine. Lysine salts and alpha-tocopheryl polyethylene glycol succinate disrupt corneal integrity, and their use requires caution. Thus a nonirritating ophthalmic solution of NSAID could be formulated by dissolving an appropriate water-soluble salt, in the presence of cyclodextrin or tromethamine (if needed) in mildly acidified purified water (if stability permits) with or without benzalkonium chloride and polyvinyl alcohol. Amide prodrugs met with mixed success due to incomplete intraocular hydrolysis. Suspension and ocular inserts appear irritating to the inflamed eye. Oil drop may be a suitable option for insoluble drugs and ointment may be used for sustained effect. Recent studies showed that the use of colloidal nanoparticle formulations and the potent COX 2 inhibitor bromfenac may enhance NSAID efficacy in eye preparations.
Aryl-2-propionic acid group of non-steroidal anti-inflammatory drugs (NSAIDs), such as protizinic acid, benoxaprofen, carprofen, and pranoprofen have been synthesised in high yields by using an undivided cell at a nickel cathode in the presence of sulphuric acid.
A facile heterogeneous synthesis of 3-amino-1-aryl-1H-naphtho[2,1-b]pyran and 2-amino-4-aryl-4H-1-benzopyran derivatives 3 and 5, respectively, was carried out efficiently by one-pot three-component coupling of an aromatic aldehyde 1, an active methylene compound 2, and naphthalen-2-ol or a phenol 4 in the presence of 5-Å molecular sieves under solvent-free microwave-irradiation conditions (Scheme 1 and 2, Tables 1 and 2). The catalyst was recovered and recycled (Table 3).
A series of functionalized H-[1]benzopyrano[2,3-b]pyridine derivatives were synthesized by the Friedländer reaction of 2-amino-4-oxo-4H-chromene-3-carbonitriles 1 with malononitrile, ethyl cyanoacetate, or acetophenone (Scheme). The synthesized compounds 2–4 were screened for their in vitro activity against antitubercular, antibacterial, and antifungal species (Fig., Table). Among the synthesized compounds, 3c and 4f were the most active with 99% inhibition against Mycobacterium tuberculosis H37Rv, while compounds 2f, 3f, and 4d exhibited 69%, 63%, and 61% inhibition, respectively. The 4-amino-7,9-dibromo-1,5-dihydro-2,5-dioxo-2H-chromeno[2,3-b]pyridine-3-carbonitrile (3b) showed the most potent antibacterial activity against Escherichia coli and Pseudomonas aeruginosa. Several chromeno[2,3-b]pyridine derivatives showed equal or more potency against Staphylococcus aureus and Candida albicans.
People with rheumatoid arthritis (RA) identify pain as their most important symptom, one that often persists despite optimal control of inflammatory disease. RA pain arises from multiple mechanisms, involving inflammation, peripheral and central pain processing and, with disease progression, structural change within the joint. Consequently, RA pain has a wide range of characteristics-constant or intermittent, localized or widespread-and is often associated with psychological distress and fatigue. Dominant pain mechanisms in an individual are identified by critical evaluation of clinical symptoms and signs, and by laboratory and imaging tests. Understanding these mechanisms is essential for effective management, although evidence from preclinical models should be interpreted with caution. A range of pharmacological analgesic and immunomodulatory agents, psychological interventions and surgery may help manage RA pain. Pain contributes importantly to the clinical assessment of inflammatory disease activity, and noninflammatory components of RA pain should be considered when gauging eligibility for or response to biologic agents. Further randomized controlled trials are required to determine the optimal usage of analgesics in RA, and novel agents with greater efficacy and lower propensity for adverse events are urgently needed. Meanwhile, targeted use of existing treatments could reduce pain in people with RA.
The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This Review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
A facile, one-pot, pseudo four-component catalyst- and solvent-free synthesis of novel benzopyrano[2,3-b]pyridines is achieved by Michael addition of various naphthols to iminocoumarin derivatives obtained from Knoevenagel condensation of salicylaldehydes with malononitrile, which can be attacked by another molecule of malononitrile to afford the title products. The advantages of this procedure are mild reaction conditions, high yields of products, generality, short reaction times and operational simplicity.
Ethnopharmacological relevance:
The seeds of Brucea javanica (L.) Merr. (Yadanzi in Chinese) have been used for the treatment of inflammation, dysentery, malaria, and cancer in Chinese traditional medicine. However, the anti-inflammatory mechanism of Brucea javanica has not been fully elucidated. This study examined the anti-inflammatory activity of ethyl acetate fraction of the seeds of Brucea javanica (EA-BJ) in vitro and in vivo.
Materials and methods:
The anti-inflammatory activity of EA-BJ and its ability to modulate the production of NO, PGE2, TNF-α, IL-1β, IL-6 and IL-10 inflammatory mediators in lipopolysaccharide-activated RAW 264.7 macrophage were evaluated. Moreover, the anti-inflammatory activity of EA-BJ was also in vivo assayed by carrageenan induced paw edema in mice.
Results:
In vitro assays showed remarkable anti-inflammatory activity of EA-BJ, through the inhibition of production of NO, PGE2, TNF-α, IL-1β and IL-6 inflammatory mediators and induction of production of IL-10 anti-inflammatory cytokine. In vivo assays showed anti-inflammatory activity for decrement of the paw edema in carrageenan induced paw edema test.
Conclusion:
The results obtained in vitro and in vivo showed that possible anti-inflammatory effects of EA-BJ may be attributed to inhibition pro-inflammatory mediators production, NO, PGE2, TNF-α, IL-1β and IL-6 and to increase production of IL-10 anti-inflammatory cytokine. The seeds of Brucea javanica may thus prove beneficial in the treatment of inflammatory diseases.
It is now widely accepted that the development of atherosclerotic lesions involves a chronic inflammatory response that includes both innate and adaptive immune mechanisms. However, it is still unclear precisely what induces the inflammatory response. Furthermore, inflammation within the blood vessel can be divided into direct mechanisms where the primary inflammatory events occur within the intima of the blood vessel and contribute to both the initiation and progression of the plaques and indirect mechanisms where inflammation at nonvascular sites can contribute to the progression of the lesions. The direct mechanisms include lipid deposition and modification, influx of lipoprotein associated factors and microparticles derived from many different cell types, and possibly bacterial and viral infection of vascular cells. Indirect mechanisms derive from inflammation related to autoimmune diseases, smoking, respiratory infection, and pollution exposure, and possibly periodontal disease and gastric infection. The mechanisms include secretion of cytokines and other inflammatory factors into the circulation with subsequent uptake into the plaques, egress and recruitment of activated inflammatory cells, formation of dysfunctional HDL and crossreactive autoantibodies.
A series of 4H-chromenes containing various modifications in the ring B and polyalkoxy substituents in the ring E has been synthesized by Knoevenagel-Michael-hetero-Thorpe-Ziegler three-component domino reaction with the overall yield of 45-82%. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antimitotic and microtubule destabilizing activity. The most active compounds 5{1,5} and 5{5,5} featured sesamol-derived ring B and m-methoxyphenyl or m-methoxymethylenedioxyphenyl ring E. Compounds 5{3,1}, 5{1,2}, 5{5,4}, 5{1,5}, and 5{5,5} exhibited strong cytotoxicity in the NCI60 human tumor cell line anticancer drug screen. Surprisingly, cell growth inhibition caused by these agents was more pronounced in the multidrug resistant NCI/ADR-RES cells than the parent OVCAR-8 cell line. The results suggest that polyalkoxy substited 4H-chromenes may prove to be advantageous for further design as anticancer agents.
Six nonsteroidal anti-inflammatory drugs (NSAIDs) in human plasma samples were analyzed by liquid chromatography (LC)-electrospray
ionizationtandem mass spectrometry (MS-MS) using a hydrophilic polymer column (MSpak GF-310 4B), which enabled direct injection
of crude biological samples. Separation of the six NSAIDs, alminoprofen, flurbiprofen, ibuprofen, pranoprofen, tiaprofenic
acid, and zaltoprofen, was carried out using gradient elution with 10 mM ammonium acetate/acetonitrile. The mass spectra obtained
by LC-single stage MS showed base peak ions due to [M+H]+ for alminoprofen, zaltoprofen, tiaprofenic acid, and pranoprofen, and [M-H]- for ibuprofen and flurbiprofen. Product ions were produced from each [M+H]+ or [M-H]- ion in the tandem mode. Quantitation was performed by multiple reaction monitoring with switching from positive to negative
ion mode and vice versa. All drugs spiked into plasma showed recoveries of 77.0%–88.2%. The regression equations for the six
drugs showed excellent linearity in the range of 0.01–25 μg/ml of plasma, and limits of detection were in the range of 0.002–0.005
μg/ml. Limits of quantitation were 0.01–0.02 μg/ml. Intraday and interday coeffi cients of variation for all drugs in plasma
were not greater than 8.1%. The accuracy of quantitating the six drugs was in the range of 94.5%–110%. Data obtained from
actual determinations of the levels of alminoprofen, pranoprofen, and ibuprofen in human plasma after oral administration
are also presented.
KeywordsNonsteroidal anti-inflammatory drugs-Hydrophilic polymer column-Ibuprofen-Pranoprofen-LC-MS-MS-Direct injection
The vascular location of an enzyme accounts for the cardiovascular hazards associated with its inhibition.
This study investigated the expression of miRNA-221 in asthmatics in order to determine whether miRNA-221 plays a role in the development of asthma. Real-time PCR was used to detect the miRNA-221 in both asthmatic and control subjects. In addition, airway inflammation was evaluated by cell counting and tissue biopsy in the OVA-induced murine asthma model. miRNA-221 was differentially expressed in asthmatics and control subjects, and miRNA-221 blockade resulted in a reduction of airway inflammation in the OVA-induced murine asthma model. We conclude that miRNA-221 participates in the pathogenesis of asthma and that inhibition of miRNA-221 suppresses airway inflammation in asthmatics.
We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first-line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA.
Although widely used, the benefits and risks of ibuprofen, especially compared with other non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, have only recently been evaluated in OA of the hip and knee in randomized-controlled clinical trials (RCT). The efficacy and occurrence of adverse reactions from ibuprofen was compared with placebo in a structural review of the literature and systematic review of RCTs in large-scale clinical trials. Ibuprofen has been found to result in approximately 50-60% improvement over placebo in WOMAC scores, including those reflecting inflammatory joint pain in knee and hip OA or other indices of pain, disability and impaired function. Mega-trials performed in comparison with the newer NSAIDs, the coxibs, have shown that ibuprofen has comparable therapeutic benefits and although serious gastrointestinal conditions are sometimes more frequent after short-term treatment, longer-term (several months) therapy in OA reduces the advantages of the coxibs over other NSAIDs including ibuprofen. Cardiovascular risk, though present with coxibs and some NSAIDs in OA, is lower or slightly so with ibuprofen compared with coxibs.
Ibuprofen is effective and relatively safe (especially at low over-the-counter doses and in the short term) for mild-to-moderate OA of the knee and hip. The PK properties of ibuprofen in OA (short plasma t½) confer advantages of this drug for OA, while evidence for clinically relevant PD benefits in joints of patients with OA, though limited, is suggestive of local anti-inflammatory activity.
Andrographolide (1) is a major diterpene lactone exhibiting anti-inflammatory effects and is found in the plant Andrographis paniculata (Burm. f) Nees, which is widely used in Traditional Chinese Medicine. Synthesis of more effective drugs from andrographolide is very interesting and can prove to be highly useful. In this study, we investigated the anti-inflammatory effects of andrographolide and its derivatives (compounds 2-6) through dimethylbenzene-induced ear edema in mice. Substances under study were administrated intragastrically and the structure-activity relationship was analyzed. Results showed that compounds 5 and 6 significantly inhibited ear edema compared with compound 1 (p<0.05), indicating that the introduction of p-Chlorobenzylidene to C-15 of compound 2 enhances the anti-inflammatory effect. Moreover, compound 6 exhibited the strongest anti-inflammatory effect against ear edema in mice (79.4%; 1.35 mmol/kg, ig) and paw edema in rats (50.4%; 0.90 mmol/kg, ig). In addition, compound 6 significantly (p<0.05) inhibited granuloma formation and reduced the increase in vascular permeability induced by peritoneal injection of 0.6% acetic acid solution in mice. Findings indicate that compound 6 exerts its enhanced anti-inflammatory effects by decreasing serum iNOS activity, NO production, and PGE(2) production.
The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
The clinical significance of pyran and pyrimidine condensed systems and the raise in problem of multidrug resistant bacterial pathogens has directed us to synthesize pyranopyrimidine derivatives via the reactions of the versatile, 2-amino-4-(4-methoxyphenyl)-4H-substituted chromene-3-carbonitrile with the appropriate reagents. The newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, Mass spectra and Elemental analysis. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H(37)Rv [ATCC-27294] and antibacterial activity against Staphylococcus aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as gram-positive, Escherichia coli [ATCC-25922] and Pseudomonas aeruginosa [MTCC-441] as gram-negative bacterial strains and antifungal activity against Aspergillus niger [MTCC-282]. Several derivatives exhibited pronounced antitubercular and antimicrobial activities.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most prescribed drugs worldwide and have now probably overtaken Helicobacter pylori as the most common cause of gastrointestinal injury in Western countries. Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies.
To provide an update on recent advances in our understanding of the cellular and molecular mechanisms involved in the development of NSAID-induced ulcers.
A Medline search was performed to identify relevant literature using search terms including 'nonsteroidal anti-inflammatory drugs, aspirin, gastric ulcer, duodenal ulcer, pathogenesis, pharmacogenetics'.
The mechanisms of NSAID-induced ulcers can be divided into topical and systemic effects and the latter may be prostaglandin-dependent (through COX inhibition) or prostaglandin-independent. Genetic factors may play an important role in determining individual predisposition.
The pathogenesis of NSAID-induced peptic ulcers is complex and multifactorial. Recent advances in cellular and molecular biology have highlighted the importance of various prostaglandin-independent mechanisms. Pharmacogenetic studies may provide further insights into the pathogenetic mechanisms of NSAID-induced ulcers and help identify patients at increased risk.
5-Oxo-5H-[1]benzopyrano[2,3-b]pyridine-3-carboxylic acids 23 and their tetrazole analogues 24 were synthesized from 4-oxo-4H-1-benzopyran-3-carbonitriles 3 or 2-amino-4-oxo-4H-1-benzopyran-3-carboxaldehydes 4. When administered intravenously, they exhibited antiallergic activity in a reaginic PCA test in rats. In the carboxylic acid series, the activity was influenced by the substituents at the 2-position and increased substantially in the following order: Me, OMe less than NH2 less than OH, H less than NHOMe. On the other hand, in the tetrazole series, 2-unsubstituted derivatives showed the highest activity. Regardless of the kinds of substituents at positions 2 and 3, compounds bearing an alkyl group, especially an isopropyl group at the 7-position, were superior in activity to the corresponding unsubstituted compounds. Among these alkyl derivatives, 3-carboxylic acid derivatives, i.e., 23c (7-ethyl), 23g (2-amino-7-isopropyl), 23r [2-(methoxyamino)-7-isopropyl], and a 3-tetrazole derivative 24c (7-isopropyl), were 41-184 times as potent as disodium cromoglycate. They also exhibited remarkable activity when administered orally; clinical studies on 23g (AA-673) are in progress.
A method is presented for measuring the edema induced by injection of 0.05 ml of 1% solution of carrageenin, an extract of Chondrus, into the plantar tissues of the hind paw of the rat. Peak edema develops within the first 3 to 4 hours, and is inhibited by pretreatment of the animals by single oral doses of antiinflammatory agents, steroid or non-steroid. Log dose responses to drugs are linear and parallel, and yield potency ratios with relatively narrow confidence limits. The potency ratios obtained for aspirin, phenylbutazone and hydrocortisone are fairly close to the ratios of their respective daily doses in the treatment of rheumatic disease. A potent antihistaminic-antiserotonin compound, cyproheptadine, is without effect on carrageenin-induced edema.
By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage and to induce apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g. Jurkat, T47D). Through structure-activity relationship (SAR) studies of the 4-aryl group, a 4- and 7-fold increase in potency was obtained from the screening hit 1a to the lead compounds 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-(dimethylamino)-4H-chromene (1c) and 2-amino-3-cyano-7-(dimethylamino)-4-(5-methyl-3-pyridyl)-4H-chromene (4e), with an EC(50) of 19 and 11 nM in the caspase activation assay in T47D breast cancer cells, respectively. The 2-amino-4-aryl-3-cyano-7-(dimethylamino)-4H-chromenes also were found to be highly active in the growth inhibition MTT assay, with GI(50) values in the low nanomolar range for compound 1c. Significantly, compound 1c was found to have a GI(50) value of 2 nM in the paclitaxel resistant, p-glycoprotein overexpressed, MES-SA/DX5 tumor cells. Functionally, compound 1c was found to be a potent inhibitor of tubulin polymerization and to effectively inhibit the binding of colchicine to tubulin. These results confirm that the cell-based caspase activation assay is a powerful tool for the discovery of potent apoptosis inducers and suggest that the 4-aryl-4H-chromenes have the potential to be developed into future anticancer agents.
To compare the anti-inflammatory and analgesic effects of topical pranoprofen 0.1% with diclofenac sodium 0.1% after strabismus surgery, 40 patients were prospectively randomized and assigned into 2 groups. Signs and symptoms of inflammation, as well as intraocular pressure (IOP) of patients, were evaluated at 1 day and 1 and 3 weeks following surgery. Both groups reported reduced inflammation and discomfort at 1 week, as compared to 1 day. There was no statistically significant difference in any measurement of postoperative inflammation (i.e., discomfort, chemosis, secretion, conjunctival hyperemia, and conjunctival gap size) between the 2 groups at any time. None of the patients developed an allergic reaction to the medications and IOP measurements were within the normal limits in both groups. Pranoprofen 0.1% was found to be as effective as diclofenac sodium 0.1% in reducing inflammation and pain after strabismus surgery. Pranoprofen could be used as a safe and effective anti-inflammatory alternative for the treatment of inflammation following strabismus surgery.
In our continuing effort to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the structure-activity relationship (SAR) of alkyl substituted pyrrole fused at the 7,8-positions. A methyl group substituted at the nitrogen in the 7-position of the pyrrole ring led to a series of potent apoptosis inducers with potency in the low nanomolar range. These compounds were also found to be low nanomolar or subnanomolar inhibitors of cell growth, and they inhibited tubulin polymerization, indicating that methylation of the 7-position nitrogen does not change the mechanism of action of these chromenes. Compound 2d was identified as a highly potent apoptosis inducer with an EC50 value of 2 nM and a highly potent inhibitor of cell growth with a GI50 value of 0.3 nM in T47D cells.
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