3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (2023)

Related terms:

  • chlormethan
  • 12-O-tetradecanoyl phorbol-13-acetate
  • tromboxan A2
  • indometacyna
  • Platelet activating factor
  • Inflammation
  • Respiratory allergy
  • Inhibitor lipoksigenaze
  • Norhydroguaiaretinsyre
  • lipoxygenase
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Approaches to new anti-arthritis drugs by modulating the arachidonic acid cascade

Rodger M. McMillan, ... John S. Shaw, wMechanisms and models in rheumatoid arthritis, 1995 (encyclopedic entry).

Redox-based inhibitors

The vast majority of patents on lipoxygenase inhibitors cover agents that have the potential to participate in redox processes. It is common experience among pharmaceutical researchers in the field that such inhibitors are easy to detect; indeed, non-specific antioxidants such as NDGA exhibit potent lipoxygenase inhibitory properties. The main disadvantage of such inhibitors is that they interfere with a large number of other redox-based enzymes. For example, an early prototype inhibitor, BW755C, inhibited both 5-lipoxygenase and cyclooxygenase, complicating the analysis of its biological effects. Zeneca (formerly ICI Pharmaceuticals) has developed more selective redox inhibitors based on indazolinones that have significantly lower redox properties than BW755C. An example of this class, ICI207968, was 300-fold more potent as an inhibitor of leukotriene biosynthesis compared to prostaglandin synthesis (appreciateme inside., 1990 (encyclopedic entry).). The compound was also orally active as an inhibitor of leukotriene biosynthesis, but ICI207968 was not developed because it caused a species-dependent induction of methemoglobin formation. In a number of analogs, methemoglobin induction was directly related to redox potential, although 5-lipoxygenase inhibition was not. Further research led to the discovery of carboxamide analogues that had a lipoxygenase inhibitory effect comparable to ICI207968in vitrobut did not induce methemoglobin (Bruneaume inside., 1991 (encyclopedic entry).). However, no analog combined sufficient oral potency with the absence of methemoglobinemia. Other companies have encountered similar problems with redox inhibitors, and agents of this class should be considered imperfect pharmacological tools. Generation and control of free radicals is discussed in detail inChapter 16, that volume.

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Five-membered rings with two heteroatoms and fused carbocyclic derivatives

Jose Elguero, f.Kemi II heterocyclisk complex, 1996 (encyclopedic entry). Dihydroactive Tautomerism and isomerization

Det factum, at 3-amino-Δ2-pyrazolines exist as such〈84CHEC-I(5)167〉and not in other tautomeric forms (iminopyrazolidine, amino-Δ3-pyrazoline) was crystallographically determined experimentally in the solid state〈88AX(C)909〉za 1-phenyl-3-amino i 1-Mtrifluormethylphenyl-3-aminoderivater (BW755C: formel 719 w〈84CHEC-I(5)167〉). 1-allyl-1-methyl-3-amino-A-omlejring2-pyrazolinij giver 1-methyl-2-allyl-3-iminopyrazolidin〈88JHC415〉. The equilibrium between 3-trimethylsilyl-Δ1-pyrazolin og 1-trimethylsilyl-D2-pyrazoline (tautomerism with associated silyltropy) is replaced by1'H NMR〈85JOM(293)177〉. Flavorings

3-methoxycarbonyl-Δ-oxidation2-pyrazoline with lead tetraacetate gives a complex mixture of compounds, including mN,N'-derivative (161).

3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (1)

Mackenzie used pyrazolines as models for intramolecular diotropyme inside. 〈87T5981, 93JCS(P2)1211〉. In a series of beautiful experiments combining kinetic isotope effects of primary deuterium and X-ray crystallography, Mackenzie shows that in suitable polycyclic systems such as (162) there is a double proton transfer to (163), which takes place by simple heating (for example melting).

3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (2)

Δ transformation1-pyrazolines containing a benzenesulfonyl group in position 3 give pyrazoles in the reaction with KOH/MeOH with loss of SO2group ph〈92T8101〉. Reduction

D reduction2-pyrazolines to pyrazolidines will be investigated with the latter compounds (see3.01.6.3). There, the Grignard reaction will be used to transform the pyrazoline (171) and (174) to 3-substituted pyrazolidines (172) and (175): one racemic diastereomer (so-calledd, l) is achieved〈92JOC4563〉. Thermolysis and pyrolysis

Termolyserer 3-aryl-l,l-dimethyl-D2-fluorboran pirazolin (164) gives the isomeric mixture of 1-methyl-3-arylpyrazole (165) og 1-methyl-5-arylopyrazol (166). The authors suggest a "normal" relationship (165) is assumed to be formed by demethylation followed by oxidation, while the isomer (166) is formed by the transmethylation reaction〈92IJC(B)172〉. Some labeling experiments support this explanation.

3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (3)

Gas phase thermolysis after 4-methylene-Δ1-pirazolin〈84CHEC-I(5)167〉continues to attract interest〈90CB1161〉. A new chelotropic process is described in which pyrazolines (168) (prepared by 1,3-dipolar cycloaddition of diphenylnitrilimine via (167)) are converted to pyrazoles (169)〈92C335〉.

3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (4)

A new class of localized biradicals, cyclobutanediyl, was synthesized from the corresponding Δ1-pyrazoline and observed by EPR spectroscopy with matrix isolation〈88JA1356〉. These pyrazolines have a methylene bridge between positions 3 and 5 (diazabicyclo[2.1.1]hex-2-enes). Bicyclic-Δ reactivity1-pyrazolines were studied by Adam〈93JA12571, 94JA7049〉. Other reactions

An unusual rearrangement transforms 3-benzoyl-Δ2-pyrazolina do fenilpyridazinon〈83H(20)2385〉. Tautomeria azydowo-tetrazolowa 3-azydo-Δ2-pirazoliny badali m.in1Hand13C NMR〈84CS195〉. Maas〈92CB1227〉described the so-called homopyrazoles (2,3-diazabicyclo[3.1.0]hex-3-enes) (170a), which exist in equilibrium with 1,4-dihydropyrazines (170b).

3 Amino 1 (3 Trifluorometilfenil) 2 Pyrazoline - overview (5)

Guy〈93AHC(58)215〉summarized the results of 1-phenyl-Δ-nitration2- pyrazolines; eg. 1,5-diphenyl-3-aryl-2-pyrazolines are nitrated with potassium nitrate in sulfuric acid to give 1-P-nitrophenyl derivative in quantitative yield. Opening of the thermal ring Δ2-Pyrazoline-3-carboxylic acids were used as a method to obtain β-aminonitriles〈94T7543〉while base-promoted ring opening of 1,1-disubstituted-3-amino-Δ2Salts of -pyrazoline give eitherN,N-disubstituted hydrazines or α,β-unsaturated amidrazones〈86SC585〉. Stereochemistry

Acid-catalyzed experiments, followed by proton NMR, show that optically active 5-substituted Δ2-pyrazolines exchange their protons with C4faster than c5the substituent (the phenyl group) epimerizes. Resolution of 1,3-dimethyl-5-phenyl-Δ2-pyrazoline was obtained by liquid chromatography on triacetyl cellulose. The exchange of protons and deuterium in deuteroacetic acid or deutero-trifluoroacetic acid shows that C4-protontransto the phenyl group is exchanged faster than the other C4-proton. C epimerisering5the substituent is defined by1H NMR in the presence of chiral lanthanide displacement reagents〈87CS283〉. Resolution of 1,3-dimethyl-5-phenyl-Δ2-pyrazoline was obtained by forming an inclusion compound with a chiral host〈95CC1453〉.

These experiments show that two mechanismscistransisomerization acts simultaneously in Δ2-pirazolin: C4epimerization and C5epimerization, with the first being the most efficient. Different proton rates for C4corresponds to the protonation of intermediate Δ3-pyrazoline through a less blocked face. Thoth〈89JCS(P2)319, 93T863〉devoted much effort to conformational analysis and Δ stereochemistry2-pirazolin.

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Models for understanding inflammation in vivo (in vivo methods of inflammation)

Poonam Negi, Saurabh Kulshrestha, žThe latest developments in anti-inflammatory treatment, 2023

5.6 Dermatitis

Many skin diseases, such as psoriasis, atopic dermatitis, contact hypersensitivity, acne, are characterized by inflammation[73]. These diseases affect more than 20% of the population, and dermatologists have developed various treatment options. Since their debut in 1952, topical corticosteroids have been the standard treatment[74]. Although these powerful anti-inflammatory drugs are effective in treating acute and chronic inflammatory skin conditions, they are not suitable for continued use in chronic conditions such as psoriasis due to side effects. Topical steroids cause the skin to shrink, which shortens the treatment time[75]. In addition, local administration of steroids over large areas of the body leads to hypothalamic-pituitary-adrenal suppression due to systemic absorption, necessitating discontinuation of treatment. In some situations, the disease returns, often in a more severe form than before the treatment. New non-steroidal anti-inflammatory drugs with efficacy comparable to topical steroids but without the side effects associated with steroids are urgently needed. Various molecular targets have been and continue to be investigated in many pharmaceutical research centers. There are many potential targets involved in inflammatory cascades, and biochemical studies can be used to find inhibitors and antagonists. Molecular targets are often selected based on increased target expression or activity in human diseases. Cytokines, lipid mediators, protein kinases, adhesion molecules and growth factors have been identified as potential sources of cancer. Potential options include cytokines, lipid mediators, protein kinases, adhesion molecules and growth factors. To assess proof-of-principle, inhibitors or antagonists are discovered and tested for efficacy in cell and animal models. An anti-inflammatory effect will be found if the target plays a major role in inflammation. One type of inflammagen that has been studied in this way is the lipid mediators of inflammation, collectively called eicosanoids. Since 1975, there has been an increase in eicosanoids in psoriatic skin[24]. Many of these substances have pro-inflammatory properties and their synthesis has been extensively studied[76]. Since arachidonic acid is a precursor of leukotrienes and prostaglandins, inhibition of phospholipase A2 activity, which releases arachidonate from membrane phospholipids, can block the entire family of mediators[77]. Using enzyme screenings, inhibitors were discovered that prevent the release of arachidonic acid in cells. This in vitro proof of concept suggests that such chemicals may be beneficial for skin diseases such as psoriasis that have high levels of leukotrienes and prostaglandins. However, psoriasis does not appear to occur naturally in animals, and there is controversy as to whether the models generated sufficiently resemble the human disease. To overcome this shortcoming, researchers have built models that simulate certain features of the pathophysiology found in the human condition. The results of such models are used to decide which drugs to test in clinical trials. Of course, human disease activity is the ultimate test of the therapeutic efficacy of new anti-inflammatory drugs for the treatment of inflammatory skin diseases. On the other hand, clinical assessments are expensive and involve many possible factors to be controlled for; therefore, they should only be used to evaluate candidates that show potential in the most stringent models available[78]. Some of the models used are described below.

5.6.1 TPA-induced dermatitis

The most common test for steroidal and non-steroidal anti-inflammatory drugs is croton oil or 12-O-tetradecanoylphorbol-13-acetate or TPA-induced skin irritation model. Croton oil has been phased out in favor of the active ingredient TPA[79]. In the case of TPA, only a single local dose applied to the ears of mice causes an edematous reaction lasting 6 hours. Phorbol esters also cause neutrophil infiltration, reaching peak levels 20-24 hours later[80]. As the acute injury heals, these reactions subside. The exact mechanism by which the phorbol ester induces inflammation is not known, although it appears to be partially related to the release of eicosanoid mediators. TPA causes a short-term increase in prostaglandin levels in the skin. Changes in vascular permeability and cellular infiltration result in increased LTB4 levels[76]. The effect of oral and topical anti-inflammatory drugs on phorbol ester-induced otitis in mice was investigated. Carlson et al. investigated the effects of several different pharmacological drugs in this animal model[81]. Betamethasone and other topical steroids are effective in preventing swelling caused by phorbol esters. Traditional NSAIDs such as indomethacin, diclofenac and piroxicam are also very effective when used topically. Agents that inhibit leukotriene production, such as prednisone, BW755c, and zileuton, are also effective. LTB4 antagonists have also been shown to be effective. Phospholipase A2 inhibitors have been shown to prevent phorbol ester-induced edema and cell infiltration. In general, cyclooxygenase and/or lipoxygenase or phospholipase A2 inhibitors that regulate eicosanoid production have local effects in this animal model. This paradigm appears to be a viable screen for in vivo evaluation of leukotriene/cyclooxygenase inhibitors that were selected by enzymatic and cellular assays based on these results. Considering that antihistamines and serotonin antagonists act locally, it is obvious that, in addition to eicosanoids, additional mediators also participate in this type of inflammation. Mast cells are a prerequisite for the full manifestation of TPA-induced increases in vascular permeability and cellular infiltration as shown in mast cell-deficient animals. The fact that antihistamines can stop the full development of the inflammatory reaction indicates that mast cells are significantly involved in the development of acute inflammation. Hydrochlorothiazide, chlorpromazine, haloperidol, and nifedipine are examples of non-traditional anti-inflammatory drugs that have shown activity. The effectiveness of this model to predict new anti-inflammatory drugs for human dermatitis has been called into question due to the activity of these latter molecules. Traditional NSAIDs can be potentially problematic. Indomethacin is ineffective in the treatment of psoriasis, whether administered orally or topically. In fact, according to one study, indomethacin worsens the disease. Before evaluating active substances as candidates for clinical trials, additional models must be investigated to eliminate these false positives[82].

5.6.2 Models of immune-mediated dermatitis

Psoriasis and atopic dermatitis are genetically determined immune diseases in which T-lymphocytes and cytokines play a key role. Recently, immunosuppressive drugs have been discovered, for example methotrexate, cyclosporin A, FK-506 and diphtheria toxin interleukin-2 fusion protein. The effectiveness of these drugs in clinical trials has led researchers to search for immunosuppressive compounds that can block the initial activation of T cells and serve as local immunosuppressants when applied topically. The most commonly used in vivo assays to assess drug-induced immunosuppression, other than transplantation models, are used to assess skin lesions and inflammatory responses in delayed hypersensitivity (DTH) models. These models represent normal cellular immune responses. People get classic DTH after infection with Mycobacterium tuberculosis. Antigen sensitivity can be induced in mice, guinea pigs and pigs. The main histological feature is lymphocytic infiltration, which occurs 4-6 hours after antigen exposure in all these animals. Extravasated plasma is present in infiltrating inflammatory cells, which explains the edema and induration seen in most DTH reactions. Anti-inflammatory and immunomodulatory drugs have been evaluated using various common methods and species[83].

5.6.3 Delayed-type hypersensitivity induced by oxazolone in mice

The mouse has long been used to test the effects of new anti-inflammatory drugs on DTH responses. DTH responses in sensitized animals can be readily assessed by measuring ear micrometer thickness or the weight gain of ears or paws after sacrifice. Histological evaluation of tissue samples or the use of a neutrophil marker such as myeloperoxidase can also be used to determine cellular infiltration. Animals are generally sensitized to the oxazole antigen by applying a solution (1-3% in acetone) to the shaved abdomen. A modest dose of oxazolone (0.5%-1%) was given to mice 4 or 5 days later to induce a DTH response. It is important to choose the challenge dose carefully so as not to cause an irritant reaction. In mice, the DTH response, a pattern of cellular infiltration, has been extensively described. Edema is significant and cellular infiltration is mild 24 hours after exposure. The numbers of mononuclear cells and PMN are almost equal (31:27). The predominance of mononuclear cells compared to PMN is evident at 48 and 72 hours (40:12 and 26:7, respectively). The DTH mouse is distinguished from other animal and human species by early and significant infiltration of PMN cells. Diapedesis of lymphocytes, with varying participation of monocytes and macrophages, is an important microscopic feature of typical human DTH. Lymphocytes are the most common infiltrating cells. Furthermore, studies have shown that most of these lymphocytes have a helper/inducer phenotype, while there are also a few killer/suppressor cells. In DTH procedures, mutant mice lacking the CD4 gene show significant hyporeactivity. DTH responses in mice have been reported to be inhibited by drugs that modify the immune system. Methotrexate, azathioprine and thioquanine are active drugs that change the activity of T cells. All these drugs inhibit cell growth and are often used in the treatment of cancer. Non-cytotoxic immunosuppressants, such as cyclosporin A and FK-506, are effective in inhibiting murine DTH. In the treatment of psoriasis, the therapy has been shown to be effective. Topical FK-506 has also shown efficacy in psoriasis and atopic dermatitis[84].

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Biology and pharmacology of platelet-12-lipoxygenase in platelets, cancer cells and their cross talk

Annalisa Contursi, ... Paola Patrignani, wBiochemical Pharmacology, 2022

7 Inhibitorni 12-LOX

Early 12-LOX inhibitors [baicalein, nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraenoic acid, OPC-29030, L-655,238 and BW755C] are not selective for 12-LOX but can also target cPLA2, COX-1, COX-2 og indre LOX (15-LOX-1, 15-LOX-2, 5-LOX)[131132135-139](table 1NDGA, BW755C and baicalein as inhibitors[140.141]. The activity of all LOX isoforms requires the activation of non-heme iron. Redox inhibitors prevent the oxidation of non-heme iron at the catalytic site and thus affect its conversion from inactive iron (Fe2+) to active iron (Fe3+)[142]. The flavonoid baicalin, the main constituent of the root of Scutellaria baicalensis, is not a selective inhibitor of 12-LOX, but also affects 15-LOX due to its catechol scaffold (table 1). Catechol alcohol binds iron and reduces the inner sphere of iron at the active site, thereby oxidizing baicalein to quinone[130]. A structurally related flavonoid, apigenin, which differs from baicalein in not containing a catechol moiety, is a non-reducing LOX inhibitor (table 1). However, it can inhibit LOX due to hydrogen bonding between its terminal alcohol group and the T591 residue. In fact, this residue can anchor apigenin in an orientation that blocks the access of iron to the substrate. Like baicalein, NDGA is a non-selective LOX inhibitor. Both compounds affect LOX with micromolar and submicromolar IC50values ​​(table 1). It has two catechol rings that provide a strong antioxidant effect; therefore trapping iron in Fe2+condition, can interrupt the redox cycle of LOX, causing their inactivation[138].

table 1. Classification of LOX inhibitors by mechanism of action.

Chemical structure and official nameTheBibliography
Inhibiting redox

Ludzki pl12-LOX, IC50=0,64 μM;
Human retikulocyt 15-LOX-1, IC50= 1.6 uM
Leukocit szczura 5-LOX, IC50=7.13 uM
Norhydroguaiaretinsyre (NDGA)

Ludzki pl12-LOX, IC50=3–5 μM
Ludzki leukocit 5-LOX, IC50=0,8 μM

Inhibitor of 12-LOX of rat leukocytes, COX-1 and 5-LOX of rabbit leukocytes (IC50not logged in)139

Gris 12-LOX, IC50=15 μM
Soja 15-LOX-1, IC50=2 μM
Human rekombinant 5-LOX, IC50= 0.10 uM

Szczur pl12-LOX, IC50= 0.063 uM
Leukocit szczura 15-LOX, IC50= 3,33 μM
Leukocit szczura 5-LOX, IC50= 1.89 uM

Rekombinant human pl12-LOX, IC50:0,5 μM;
Rekombinant human 15-LOX-1, IC50: 0,3 μM;
Rekombinant human 5-LOX, IC50: 0.015 uM




Szczur pl12-LOX, IC50=0,65 μM;
COX-1 rat platelet, IC50=450 μM;
Humane 5-LOX leukocytter, IC50=0,4 μM
Fatty acid analogues
Kwas 5,8,11,14-enabled (NOVO)

5,8,11,14-eicosatetraenoic acid
Ludzki pl12-LOX, IC50=0,03 µM,
Owca COX, IC50=3,2 μM

4,7,10,13-eicosatetraenoic acid
Ludzki pl12-LOX, IC50=0,009 μM,
Owca COX, IC50= 8 μM
Translocation inhibitors

Ludzki pl12-LOX, IC50=0,06 μM;
no effect on COX-1 activity in human platelets;
50% inhibition of 5S-HETE production at 0.1-10 μM in rat basophilic leukemia cells

Ludzki pl12-LOX, IC50=0,171 μM
5-LOX, IC50= 0.135 μM (basophilic rat leukemia cells)
Non-reducing, non-competitive inhibitors

Ludzki pl12-LOX, IC50= 0.80 uM
Human retikulocyt 15-LOX-1, IC50=>25 μM

Ludzki pl12-LOX, IC50= 1 μM
Human retikulocyt 15-LOX-1, IC50=> 100 uM
Humanepitel 15-LOX-2, IC50=> 100 uM
Human rekombinant 5-LOX, IC50=> 100 uM

Ludzki pl12-LOX, IC50=0,34 μM
Human retikulocyt 15-LOX-1, IC50=9,7 μM
Humanepitel 15-LOX-2, IC50=> 100 uM
Human rekombinant 5-LOX, IC50=> 100 uM
COX = no inhibition at test concentration (15 μM)
Other mechanisms

Ludzki pl12-LOX, IC50= 81 uM
Human retikulocyt 15-LOX-1, IC50=3,4 μM

The compound N-(4-chlorophenyl)-N-hydroxy-N′-(3-chlorophenyl)urea (CPHU), can reduce various LOX and stimulate lipid hydroperoxide degradation (table 1)[135]. Since phenols and hydroxamates react with the iron center in LOX[135], are poor choices as potentially specific inhibitors.

Another subgroup of LOX inhibitors are fatty acid analogs (table 1). Sun i sur.[143]synthesized a series of acetylenic fatty acids. One of them, 5,8,11,14-eicosatetraynoic acid (ETYA), provided a COX and 12-LOX inhibitor. In contrast, 4,7,10,13-ETYA was found to be a potent and selective inhibitor of p12-LOX. 5,8,11,14-ETYA was ten times more potent than 4,7,10,13-ETYA in inhibiting AA-induced aggregation in PRP and washed platelets[143].

Another class of 12-LOX inhibitors are 12-LOX translocation inhibitors (OPC-29030 and L-655,238) (table 1)[51]. They were synthesized to inhibit the translocation of 12-LOX to the glycerophospholipid membrane involved in the synthesis of 12-HETE. These compounds can block the formation of 12-HETE without directly inhibiting enzyme activity. In response to U46619 (TXA2mimetic) stimulationin vitro, platelets treated with OPC-29030 have a decrease in Ca2+mobilization, granulation secretion, activation and aggregation of aIIbb3 compared to control platelets resulting in reduced thrombus formation in canine models of thrombosis[51].

By using all these LOX inhibitors, we could understand the effect of p12-LOX on increasing platelet activationin vitro. Indeed, they reduced platelet activation and aggregation in response to a wide variety of platelet agonists, including collagen, thrombin, ADP, and U46619[67], but their lack of selectivity limited themDirectutility.

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Overview of the ethnomedicinal use, chemistry and pharmacological properties of the genus Acanthus (Acanthaceae)

Patrícia Matos, ... Artur Figueirinha, iJournal of Ethnopharmacology, 2022

5.3 Anti-inflammatory effect

A. ebracteatusAqueous and ethanolic leaf extracts inhibited 5-LOX (Laupattarakasem et al., 2003 (monograph).), supporting its traditional use to alleviate diseases associated with joint inflammation, in which leukotrienes play a major role.

ToA. shaggysubsp.Syrian(Boiss.) Brummitt's aerial part, ethanol extract, fraction containing ferulic acid (27.5%), chromic acid (48.1%) and chlorogenic acid (24.4%) and chromic acid were evaluated for anti-inflammatory activity in mouse model using carrageenan paw edema sample. The extract (50, 100 and 150 mg/kg), the fraction and chromic acid (5, 10 and 20 mg/kg) showed a dose-dependent improvement in edema (Rafat, 2019).

methanol extract fromA. ilicifoliusThe leaf (200 and 400 mg/kg body weight) has been reported to have anti-inflammatory and analgesic properties. It inhibited rat paw edema as well as BW755C, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX) (Kumar et al., 2008 (encyclopedia entry).). This extract also reduced gastric lesions in rats induced by ulcerative aspirin, indomethacin, ethanol, stress and pyloric ligation. It has been confirmed to reduce stomach volume, acidity and digestion, thus protecting the stomach lining (Kumar, 2012 (encyclopedia entry).), supporting the ethnomedicinal use of this plant to relieve abdominal pain.

WConditionleaves, the 96% ethanol extract showed anti-inflammatory potential with a significant reduction in nitrite production (IC50=28.01 μg/ml) in RAW 264.7 macrophages. In addition, enzyme studies have shown that this extract can inhibit LOX (Matoš et al., 2018 (encyclopedic entry).). Petroleum ether extract (100 μg/ml) showed an inhibitory effect (80-100%) on pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha).IN)and interleukin-1B,and interleukin-6 in human monocytes (Bremner et al., 2009 (encyclopedia entry).). In another study, a methanolic leaf extract (200 µg/ml) inhibited 5-LOX and COX-1 activity in rat polymorphonuclear leukocytes and increased the biosynthesis of 15 (S)-HETE, an anti-inflammatory eicosanoid (Bader et al., 2015 (encyclopedic entry).).

A. montanusaqueous leaf extract (200 mg/kg bw) significantly reduced carrageenan-induced edema in rats within 60 minutes (62.50%) (Asongal et al., 2004 (encyclopedic entry).), greater reduction than 10 mg/kg indomethacin (21.87%). Aqueous root extract also inhibited local acute edema (57%) in mouse ears and vascular permeability induced by acetic acid in mice. Regarding phagocytic activity, the extract significantly increased the number of macrophages and inhibited the delayed hypersensitivity reaction (DTHR) after administrationCandida albicansin a dose of 800 mg/kg body weight (Oko I in., 2008). Recently, methanol leaf extract (1.25, 2.5, and 5 μg/ml) inhibited COX-2 expression, TNF-α, interleukin 6, and nitric oxide (NO) release in lipopolysaccharide-stimulated J774A.1 macrophages (Pompermaier et al., 2018 (encyclopedia entry).).

Research was conducted into the anti-inflammatory effect, i.a.A. ebracteatus,A. shaggy,A. ilicifolius,ConditionandA. montanusspecies. Research on anti-inflammatory activity was mainly carried out on alcoholic extracts from the leavesin vitroLubDirect, to assess acute anti-inflammatory activity. The most common mechanisms of action are inhibition of COX and/or LOX enzymes and inhibition of pro-inflammatory cytokines, the amount of which increases with age and contributes to chronic diseases. These results suggest a beneficial effect on acute and chronic inflammationAccountantspp. listed.

Some isolated benzoxazinoids izAccountanthave also been identified as anti-inflammatory agents. DIBOA (16) showed anti-inflammatory activity in RAW 264.7 macrophages (IC50≈5μg/ml) (Matoš et al., 2018 (encyclopedic entry).) in HBOA (17) showed activity at a dose of 20 mg/kg body weight in the rat paw edema test induced by carrageenan (Zheng et al., 2015 (encyclopedia entry).). Many other compounds are associated with anti-inflammatory effectsin vitroLubi live,such as aurantamide acetate (27) (Chen et al., 2016 (encyclopedia entry).), protocatechuic syre (115) og shikiminsyre (124) (Al-Malki, 2019;Masella et al., 2012), several flavonoids such as apigenin (29), whitexyna (32), vicenin-2 (34) i linarin (35) (Ali and others, 2017 (encyclopedic entry).;On 1 July 2016;Huang i in., 2020;Pan i in., 2019;Peng i in., 2021), phenylethanoids such as acteoside (76), izoakteozid (77), kampneozid II (78), leukoseptozide A (83), martinozid (84), klorogenska kiselina (85) i dekawoilolakteozyd (Hagar i Cankaya, 2020;Naveed i in., 2018;Tian i in., 2021;Wu i in., 2020;Żyżelewicz et al., 2020) and stigmasterol steroids (103) andB-sitosterol (Babu i Jayaraman, 2020;Beat i in., 2006;Khan i in., 2020). However, there are few known anti-inflammatory mechanisms. The activities of acteoside, isoacteoside, campneoside II, leukoskeptoside A, martinoside, chlorogenic acid and decafeoyllacteoside are often associated with inhibition of the MAPK, NF-κB and JAK-STAT pathways and activation of the Nrf2 pathway. The structure-activity relationship suggests that compounds with two adjacent hydroxyl groups show better activity and compounds with two sugar groups have weaker activity than the others (Wu i in., 2020).

Bioavailability studies that could support this effectDirectare rare. Four phenylpropanoids: acteoside, isoacteoside, martinoside and crenatoside (87) was evaluated in rat plasma after intragastric administration. Although these compounds have a similar molecular structure, they showed different half-lives (Zhang i in., 2019). Other compounds such as linarin (35) (Feng et al., 2014 (encyclopedia entry).) and phytosterols (Kim et al., 2016 (encyclopedia entry).), showed low oral bioavailability, while aurantamide acetate crossed the blood-brain barrier but showed rapid metabolism (Chen et al., 2016 (encyclopedia entry).).

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