Standard Drug Indomethacin Research Articles

Design, Synthesis, Anti-inflammatory Evaluation and In silico Molecular Docking of Novel Furan-based Derivatives as Potential TNF-α Production Inhibitors

Introduction: Inflammation is the first response and an alarming signal for the onset of chronic disease. Most of the anti-inflammatory drugs available in the market are reported to have undesirable gastrointestinal toxicities. Therefore, it is of urgent significance to develop anti-inflammatory drugs with low toxicity and good efficacy. Methods: We created a targeted scaffold based on a literature review by combining the different structural characteristics of furan and benzyl amides into a single pharmacophore. A series of eighteen furanbased derivatives (1-18) were designed, synthesized for in vitro and in vivo anti-inflammatory activity. The characterization of synthesized compounds was elucidated by techniques like 1H-NMR, 13C-NMR, FT-IR and MS. Results: The synthetic compounds were examined through molecular docking studies on TNF-α for probable binding mode and interactions with hydrophilic and hydrophobic pocket of TNF-α in comparison to standard drug (Indomethacin). Conclusion: When compared to the standard treatment, compounds 18, 15 and 9 displayed a remarkable inhibitory effect on the production of TNF-α and in vivo inflammatory activity with no damage to stomach and reduction of LPO. The compounds 18, 15 and 9 might be a good consideration for potential antiinflammatory agents.

Bergenin nano-lipid carrier to improve the oral delivery: Development, optimization, in vitro and in vivo evaluation

This study aimed to prepare bergenin (BN) loaded nanostructured lipid carrier (NLC) to improve oral therapeutic efficacy. The preparation of BNNLC involved the utilization of melt-emulsification and ultrasonication techniques, followed by optimization using Box-Behnken design (BBD). The independent factors in this study were the concentration of total lipids (A), surfactant (B), and sonication duration (C). The impacts of these factors were assessed on the dependent variables, namely particle size (PS, Y1) and entrapment efficiency (EE, Y2). The optimized BN nano-lipid carrier (BNNLCo) has shown a PS of 174.3 ± 5.4 nm, EE of 80.6 ± 1.92 %, polydispersity index (PDI) of 0.086 and zeta potential of −35.6 ± 3.61 mV. The solid-state characterization results showed that BN was completely encapsulated into the NLC matrix. The BNNLCo exhibited a significant (P < 0.05) sustained release (74.2 ± 3.9 %) than pure BN. The Korsmeyer-Peppas model (R2 = 0.9326) was found to be the best-fit kinetic model. Further, it was depicted that the formulation exhibited 3.2-fold higher intestinal flux than pure BN due to enhanced permeation across the tested membrane. The relative bioavailability results of BNNLCo displayed a significantly higher (4.27-fold) bioavailability as compared to pure BN. The highest reduction in swelling was obtained with the optimized formulation (71.78 % in 6 h) as compared to pure BN (46.65 % in 4 h) and standard drug indomethacin (65.76 % in 3 h). The effect of the formulation was sustained up to 12 h (51.54 %). Our findings concluded that incorporating BN in the NLC matrix could be an alternative system for the improvement of therapeutic efficacy.

Design, Synthesis, Drug-Likeness, anti-Inflammatory, Antimicrobial Activity, and Molecular Docking Studies of Pyrimidine Analogs

Grounded on medicinal significances of pyrimidines, herein we are reporting initially the design and synthesis of 1-(2-benzylthiopyrimidin-4-yl)-benzimidazol-2-thioacetic acid/thioacetate 2(a, b), 1-(2-benzylthiopyrimidin-4-yl)-3,5 diaryl-2-pyrazoline (3) and 1-(2-benzylthiopyrimidin-4-yl)-3,5-dimethylpyrazole (4). In silico screening such as molecular docking studies of these compounds with inflammation-causing enzyme cyclooxagenase-2 (COX-2) suggests that only 2a has shown a strong affinity for the COX-2 (−9.0 kcal/mol) and forms three hydrogen bonds with active amino acid residues in comparison with standard anti-inflammatory drugs celecoxib (-8.8 kcal/mol) and indomethacin (-7.7 kcal/mol). However, in vitro, anti-inflammatory activity reveals that IC50 of compound 2a was 3.5 μM compared to celecoxib with IC50 of 0.65 μM. Also, 2a has displayed comparable activity of standard antibacterial drug gentamycin against E. coli with MIC 6.5 μM. Furthermore, the drug-likeness of potent compounds was studied using Swiss ADME and Mol inspiration software. All the compounds showed optimum drug-likeness without violating Lipinski’s rule of five. With our best observation and based on comparative SAR studies of these analogs with celecoxib and indomethacin, we conclude that compound 2a could develop as a therapeutically potent anti-inflammatory agent.

Linker-Based Pharmacophoric Design and Semisynthesis of Labdane Conjugates Active against Multi-Faceted Inflammatory Targets.

Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer's, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC50 = 17.67 ± 0.89 μM), with a 4-fold increased activity relative to the standard drug indomethacin (IC50 = 67.16 ± 0.17 μM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.

Synthesis and Evaluation of Antiphlogistic Activity of Some New 4-Fluorophenyltriazolothiadiazines

The reaction between 4-fluorobenzoic acid hydrazide (1) and carbon disulfide in the existence of alcoholic potassium hydroxide yielded N?-(4-fluoro-benzoyl)-hydrazinecarbodithioic acid (2). Subsequently, product 2 on reaction with an aqueous solution of hydrazine hydrate led to the formation of compound 3. The condensation of compound 3 with various substituted ?-bromoacetophenones in ethanol furnished the targeted triazolothiadiazines, bearing a 4-fluorophenyl moiety (4a-l). Subsequently, a comprehensive evaluation of the antiphlogistic potential of the synthesized molecules 4a-l was conducted. This assessment was completed using albino Wistar rats that had their paws swollen with carrageenan. Compounds 4l and 4b demonstrated significant (P &lt; 0.01) antiphlogistic activity. Furthermore, compounds 4d, 4f, and 4k exhibited noteworthy antiphlogistic effects (P &lt; 0.05), comparable to the standard drug indomethacin. This study sheds light on the antiphlogistic properties of these compounds and holds promise for further research in this area. . KEYWORDS :Antiphlogistic, Anti-inflammatory, 4-Fluorophenyl, Triazole, Thiadiazine.

Effective separation of maslinic acid and oleanolic acid from olive pomace using high-speed shear off-line coupled with high-speed countercurrent chromatography and their antibacterial activity test

In this work, a high-speed shear extraction off-line coupling high-speed countercurrent chromatography method was developed to separate maslinic acid and oleanolic acid from olive pomace. To improve extraction efficiency, the polar disparity between maslinic acid and oleanolic acid necessitated the concurrent utilization of both polar and non-polar solvents during high-speed shear extraction. Then, the high-speed shear extraction was directly feed to high-speed countercurrent chromatography for subsequently separation. A total of 250 min were needed to complete the extraction and separation process. This yielded two molecules from 3.3 g of defatted olive pomace: 7.2 mg of 93.8 % pure maslinic acid and 2.3 mg of 90.1 % pure oleanolic acid, both determined by HPLC at 210 nm. Furthermore, the compounds exhibited inhibitory activity against Escherichia coli and Staphylococcus aureus. At a concentration of 100 μg/mL, its efficacy in inhibiting hyaluronidase was comparable to that of the standard drug indomethacin. Compared with the conventional separation method, this coupled technique reduced the whole time due to the direct injection of sample extraction solution. This technique provides a useful approach for the separation of natural products with significant polarity differences.

Exploring the Anti‐Inflammatory Potential of Ajuga integrifolia Leaves Extract: In Vitro Dual Inhibition of Cyclooxygenase and Lipoxygenase Enzymes

This study investigated the anti‐inflammatory properties of Ajuga integrifolia, an herbal preparation. Qualitative and quantitative phytochemical analyses were conducted to identify active compounds in the preparation. The researchers also assessed its ability to inhibit the production of pro‐inflammatory enzymes, cyclooxygenases (COX‐1, COX‐2), and lipoxygenase (5‐LOX) in vitro. The extracts demonstrated dose‐dependent inhibition of these enzymes, with some extracts showing IC50 values comparable to standard anti‐inflammatory drugs. The ethanol extract exhibited significant inhibition of 5‐LOX (52.99 μg/mL), compared to the standard drug zileuton (32.41 μg/mL), while the inhibition of COX‐1 (66.00 μg/mL) and COX‐2 (71.62 μg/mL) was comparable to the standard drug indomethacin (40.57 and 54.39 μg/mL, respectively). These findings suggest that A. integrifolia has the potential to be used as a herbal remedy for treating inflammatory conditions. By inhibiting pro‐inflammatory enzymes, the extracts may effectively reduce inflammation and promote tissue healing or repair. The inhibition potential of extract of this plant can be taken as a good candidate of anti‐inflammatory agent.

Pharmacological evaluation of 2-(2-hydroxy phenylimino)-N-(2-chlorophenyl)-5-isopropyl-4-methylthiophene-3-carboxamide compound for anti-inflammatory activity in rats

Background: Thiophene, also known as thiofuran, is a heterocyclic molecule represented by the chemical formula C4H4S. Aims and Objectives: The aim of this study was to evaluate the anti-inflammatory activity of 2-(2-hydroxy phenylimino)-N-(2-chlorophenyl)-5-isopropyl-4-methylthiophene-3-carboxamide compound in Wistar rats by acute carrageenan-induced paw edema and chronic cotton pellet-induced granuloma methods. Materials and Methods: This study consists of two stages: An acute inflammation study using carrageenan-induced paw edema in rats, which involves four groups of rats, and a chronic inflammation study using cotton pellet-induced granuloma, which involves three groups of rats. Mean paw edema volume and percentage of inhibition were measured in acute stage. The mean weight of the pellets in each group was determined during the chronic stage. Results: There was increase in the mean paw volume at 3 h and a slow decrease at 6 h and 24 h in control group to thiophene derivative-20 mg/kg/p.o from 0 h to 24 h. The mean difference from control and at 3 h, 6 h, and 24 h showed that mean difference was slowly decreased and it was statistically significant. The mean dry granuloma weight in control group, i.e., 10% tween 80 treated group was 146.6 ± 4.38. The mean dry granuloma weight in standard group, i.e., indomethacin 3 mg/kg treated group was 87.7 ± 3.41. The mean dry granuloma weight in substituted thiophene 10 mg/kg group was 101.91 ± 3.76. Conclusions: The newly synthesized substituted (fused) thiophene compound demonstrated inhibition of inflammation in both acute inflammation induced by carrageenan-induced paw edema and chronic inflammation induced by cotton pellet-induced granuloma in Wistar rats. The compound’s anti-inflammatory effects were comparable to those of the standard drug indomethacin, with a dosage of 10 mg/kg in the acute model and 3 mg/kg in the chronic inflammation model. This concludes that the test compound has anti-inflammatory activity.

In Vivo Evaluation of Sothaghna Karma (Anti-Inflammatory Activity) of Bilwa (Aegle marmelos Corr.) Moola Twak and Patra - A Comparative Study

One of the characteristics of living tissues is its ability to react to injury, there occurs Inflammation. Inflammation is identified as a symptom according to modern science, whereas in Ayurveda, it is correlated to Sotha, considered as a separate clinical condition, mentioning its Lakshana’s (Signs &amp; Symptoms) and Upadrava (Complications) in relation with several ailments. Since ancient times, human societies have searched several Sotha Hara Dravyas. In the literature of Ayurveda, Bilwa (Aegle marmelos Corr.) is mentioned as one of the Shwayathuhara / Sotha Hara Dravyas among Charaka Daseimani Ganas. The present study is taken up to evaluate the comparative Sothaghna Karma (Anti-inflammatory activity) of Bilwa Moola Twak and Patra of different solvent extracts to standard drug Indomethacin suspension in four different groups of albino rats. On statistical analysis of data Trial drug A when compared with Standard drug, the resultant ‘t’ value showed insignificant difference at P &gt; 0.05. Trial drug B when compared with Standard drug, the resultant ‘t’ value showed insignificant difference at P &gt; 0.05. Both trial drugs and standard drug showed similar results, where as Bilwa Moola Twak Kashaya and Patra Swarasa has significant action in inhibiting inflammation. Trial drugs in 2nd and 3rd groups showed insignificant difference, having similar anti q-inflammatory action. Based on the observations made and results obtained statistically, the Bilwa Moola Twak can be replaced with Patra for inhibiting Sotha.

ANTI-INFLAMMATORY ACTIVITY OF SIDDHA POLYHERBAL FORMULATION SEVVIYADHI CHOORANAM ON CARRAGEENAN INDUCED PAW EDEMA IN WISTAR ALBINO RATS

Objective: The aim of the study was to explore the anti-inflammatory activity of Siddha polyherbal formulation Sevviyadhi chooranam in Carrageenan induced paw edema in wistar albino rats, and compared with the standard drug Indomethacin. Methods: The Siddha polyherbal formulation Sevviyadhi chooranam indicated for sinusitis was prepared based on GMP (Good Clinical Practice) guidelines. Study procedure was approved by Institutional Animal Ethics Committee (IAEC). The experimental animals were measured for paw edema volume at 1, 2, 3, 4, 5 h using Plethysmometer (Model 7150 UGO Basile, Italy). Edema was expressed as mean increase in paw volume relative to control animals. And then, findings were compared with Indomethacin (Standard drug). Results: The findings revealed that test drug Sevviyadhi chooranam at higher dosage 200 mg/kg (Group V) had equal effect on anti-inflammatory activity with percentage protection of 93.2% when compared with the standard drug Indomethacin at about 40 mg/kg (Group III) with percentage protection 93.2%. However, the test drug Sevviyadhi chooranam at a higher dosage 200 mg/kg (Group V) with a percentage protection 93.2% was highly effective when compared with lower dosage about 100 mg/kg (Group IV) with a percentage protection 27.12%. Hence, the study resulted that the Siddha polyherbal formulation Sevviyadhi chooranam has an optimistic anti-inflammatory activity with more therapeutic value. Conclusion: The study concluded that the Siddha polyherbal formulation Sevviyadhi chooranam has a promising anti-inflammatory activity, probably due to the presence of biologically active phytocompounds. However, it is important to admit that there are some scientific evidences of the potential actions of these phytocompounds in anti-inflammatory activity.

Anti-inflammatory Activity of the Phenolic Compounds from Vanda roxburghii R. Br.

Inflammation is implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD). Vanda roxburghii R. Br. is used as folk medicine in the treatment of various ailments and diseases including inflammation, rheumatoid arthritis and neurological disorders. We reported earlier that the plant possesses anti-inflammatory activity and the activity is high in the chloroform fraction among other fractions tested. Therefore, the present work was designed to isolate the compounds from the chloroform fraction responsible for anti-inflammatory activity. Four compounds namely syringaldehyde (1), vanillin (2), dihydroconiferyl dihydro-p-coumarate and (3) and gigantol (4) were isolated and purified using chromatographic methods. The isolated compounds were identified by analysis of their NMR spectral data. The compounds were evaluated for anti-inflammatory activity using carrageenan-induced hind paw edema model in mice. All the compounds showed significant activity at a dose of 100 mg/kg. Among the compounds, gigantol displayed the highest activity which was comparable to the activity of the standard drug indomethacin. At the same dose the other three compounds syringaldehyde, vanillin and dihydroconiferyl dihydro-p-coumarate exhibited similar activity. These results suggest that the isolated compounds from the chloroform fraction have potential anti-inflammatory activity that might be useful in the prevention and treatment of AD. Bangladesh Pharmaceutical Journal 26(1): 1-6, 2023 (January)

Exploring the anti-inflammatory potential of Colocasia esculenta root extract in in-vitro and in-vivo models of inflammation

Ethnopharmacological relevanceColocasia esculenta (CE) (L.) Schott is an annual herbaceous tropical plant from the family of Araceae which has been traditionally used for the healing of various ailments such as asthma, arthritis, internal hemorrhage, diarrhea, and neurological disorders. The plant is reported to have potential anti-microbial, anti-fungal, antimetastatic, anti-hepatotoxic, and anti-lipid peroxidative activities. Aim of the studyThe present study is designed to explore the potential anti-inflammatory property of Colocasia esculenta methanolic root extract (CEMRE) on carrageenan-induced rat paw edema and lipopolysaccharide (LPS) stimulated RAW264.7 cells. Materials and methodsCarrageenan-induced rat paw edema model was used to investigate the in vivo anti-inflammatory action of CEMRE. Adult male Wistar rats (180–220 g; n = 6) were pre-treated with CEMRE (100, 200, and 400 mg/kg BW) orally before 1 h of injection of 1% carrageenan. Indomethacin (10 mg/kg BW) was given orally as the standard drug. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), nitric oxide (NO), prostaglandinE2 (PGE2), and cytokines levels were measured. Liquid chromatography-mass spectrometry (LC-MS) was done to identify the phytoconstituents present in CEMRE. The inhibitory activity of CEMRE was investigated against cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in in vitro assessment of LPS-stimulated RAW264.7 cells. The RAW 264.7 cells were pre-treated with Indomethacin (5 μM and 10 μM) and CEMRE (17 μg/ml and 34 μg/ml) followed by induction of LPS (1 μg/ml) for 24 h. Docking analyses were also performed to explore the interaction of important phytoconstituents (Sinapic acid, Acetylsalicylic acid, L-fucose, Salicylic acid, Quinic acid, Zingerone, and Gingerol) of CEMRE with COX-2 and iNOS. ResultsPre-treatment with CEMRE (400 mg/kg) could inhibit the paw inflammation significantly which was elevated due to carrageenan induction. The inhibition is comparable to that of the standard drug Indomethacin. The concentration of serum AST, ALT, ALP, NO, PGE2 and cytokines were also considerably lowered in the CEMRE-treated group as compared to the carrageenan-induced group. CEMRE (34 μg/ml) inhibited the LPS-stimulated relative expression of mRNA of COX-2 and iNOS and significantly reduced the expression of nitric oxide and prostaglandin E2. Docking analyses revealed promising interaction with low binding energies between Sinapic acid with both the target proteins COX-2 and iNOS. ConclusionCollectively, our results suggested that CEMRE exhibited effective anti-inflammatory actions on carrageenan-induced rat paw edema and LPS-treated RAW 264.7 cells by reducing the in vivo paw edema inhibition, inhibiting the serum NO, PGE2, cytokines and also reduced the in vitro production of NO, PGE2 along with expressions of mRNA COX-2 and iNOS. Molecular docking demonstrated good binding affinities among the target proteins and ligand Sinapic acid. Thus the bioactive compound from CE need to be isolated and purified.

Design and synthesis of anti–inflammatory 1,2,3–triazolylpyrrolobenzodiazepinone derivatives and impact of molecular structure on COX–2 selective targeting

COX–2, a key enzyme that catalyzes the rate–limiting steps in the conversion of arachidonic acid to prostaglandins, plays a pivotal role in the inflammatory process. Therapeutic utilization of selective COX–2 inhibitors has been considered an effective approach for treating inflammation with emasculated side effects. This study describes the design and enantioselective synthesis of a library of twenty–six novel 1,2,3–triazolylpyrrolobenzodiazepinone derivatives. The molecules were found to exhibit good drug–like properties as implied by the ADMET studies. Nine compounds of the library showing promising results in silico studies were evaluated for cell toxicity on HeLa cells and in vitro COX–1/COX–2 enzyme inhibition. Compounds (2b) and (4l) were found to significantly inhibit COX–2 in vitro in comparison to the standard and compound (4l) with S–geometry showed extraordinary COX–2 inhibition (IC50 = 18.9 nM) and the best selectivity (COX–1/COX–2 = 1060). (4l) also exhibited the most potent anti–inflammatory activity in vivo in comparison to the standard drugs (Indomethacin and Celecoxib) without inducing any gastric ulceration. Molecular modeling studies aided in the understanding of the interaction modes between this compound and the COX–2 enzyme. Findings in this study may thus serve as a pivotal avenue for developing next–generation selective COX–2 anti–inflammatory drugs using pyrrolobenzodiazepinone (PBD), scaffold.

Synthesis; Characterization and Anti Inflammatory Activity of “3-(2-[1H Benzimidazole-2-YL)-2-Oxethyl] Phenyl) Acetic Acid and Its Derivatives”

A series of five-membered heterocyclic rings like Benzimidazole were synthesized by the reaction between benzene-1, 2 diamine and formic acid to form various Benzimidazole derivatives (BD- BK) compounds and was tested for their anti-inflammatory activity determined by rat-paw- oedema method. All the synthesis compounds have been characterized by 1HNMR, IR and some Mass spectral data. The compounds were purified by recrystallization method. The entire compound gives good response for the anti-inflammatory activity: Benzimidazole (AA), 1-(1H-benzimidazol-2-yl)-2-(3-hydroxyphenyl) ethanone (AC); 2-{3-[2-(1H-benzimidazol-2-yl)-2-oxoethyl] phenyl}-N-phenylacetamide (AJ); 2-{3-[2-(1H-benzimidazol-2-yl)-2-oxoethyl] phenyl}-N-(2-nitrophenyl) acetamide (AK); 2-{3-[2-(1H-benzimidazol-2-yl)-2-oxoethyl] phenyl}-N-(3-nitrophenyl) acetamide (AL). For this anti-inflammatory activity, Indometacin was used as a standard drug and compared to new synthesized drugs. Some new synthesized drugs have shown better activities for the anti-inflammation. The synthesize compounds were establish to be AA to AL. The compound AA, AC, AJ, AK and AL were established to be the most potent compound through compare to standard drugs Indomethacin.

In vivo and In silico Anti Inflammatory Studies of Alstonia scholaris Bark Extract

The present research is focused on screening In vivo anti-inflammatory activity using carrageen and formalin induced paw edema model in rodents and In silico approaches like docking studies (mcule), Ramchandran plot (procheck) and PASS. The extract significantly inhibited inflammation caused by carrageenan and formalin at doses of 200 mg and 400 mg/kg body weight which is compared to the the effect of the standard drugs meloxicam and indomethacin. Docking studies for natural compounds were carried out against PDB ID: 2AZ5, PDB ID: 1IBC, PDB ID: 6COX, and PDB ID: 4NOS in order to assess the ligand-binding affinity of the active principles of the extract. The docking results showed that the phytoconstituents from the extract and standard drugs meloxicam and indomethacin had shown highest glide scores with all the selected proteins which indicate a greater affinity for binding between receptor and ligand. From the PASS results the possible interventions of selected active constituents of Alstonia scholaris were found to be anti- inflammatory intestinal, Prostaglandin-E2 9-reductase inhibitor, TNF expression inhibitor, Cyclooxygenase 1 and 2 inhibitors, NOS2 expression inhibitor, and Interleukin1 and 6 antagonists. From the prediction results of adverse effects the constituents like Stigmasterol, Diospyrolide, D-Friedoolean-14-en-3-one and Lupeol acetate were found to be free from any adverse effects. All the constituents of Alstonia scholaris were found to have interventions either as direct targets or possible targets with Histamine H2 receptor, Arachidonate 5-lipoxygenase, Interleukin-1 receptor-associated kinase 3 TNF-alpha, Cyclooxygenase 1, Prostanoid EP2 receptor, Prostaglandin E synthase, and Serotonin 1e (5-HT1e) receptor. From In vivo and In silico results it is evident that ethanolic bark extract of Alstonia scholaris possessed significant anti-inflammatory activity.

Factorial design in the optimization and study 'in combo' of derivatives of imidazo[1,2-a]azines in the COX´s isoforms inhibition.

Background: Imidazo[1,2-a]azines with an acid group decrease inflammatory processes in murine models, and the effect has been attributed to the inhibition of COX enzymes. Results: The optimization of a series of imidazo[1,2-a]azines was performed using the reduced factorial design 23-1. The inhibitory effects of five acid derivatives of imidazo[1,2-a]azines and the standard drugs ibuprofen and indomethacin were evaluated in vitro on COX isoforms. It was observed that the different substituents provided different inhibition profiles, highlighting that the imidazo[1,2-a]pyridines are more active than the bioisosteric imidazo[1,2-a]pyrimidines. These results were analyzed using in silico docking to recognize the structural elements necessary for the inhibition of the targets. The IC50 values for COX1 and COX2 for the various compounds were as follows. COX1: 4a = 2.72 μM, 4b = 3.94 μM, 5a = 7.29μM, 5b = 63.26 μM, 6a = 12.93 μM, indomethacin = 0.13 μM, ibuprofen = 0.2 μM; COX 2: 4a = 1.89 μM, 4b = 2.39 μM, 5a = 8.08 μM, 5b = 41.15 μM, 6a = 5.86 μM, indomethacin = 0.09 μM, ibuprofen = 0.125 μM. Conclusion: Through factorial design it was possible to optimize the inhibitory response on therapeutic targets, obtaining molecule 4a as a result of factorial analysis.

Rational drug design, synthesis, and in vivo biological activity of new indolyl-imidazolone hybrids as potential and safer non-steroidal anti-inflammatory agents

ObjectivesThe study aimed to synthesize and evaluate the potential anti-inflammatory and analgesic activities of rationally designed hybrid molecules of imidazolone and indole nuclei linked through a methylene bridge. MethodsIndolyl-imidazolone hybrids were synthesized in three simple steps starting from 2-phenyl-1H-indole (1). In the first step, compound 1 was converted to 2-phenyl-1H-indole-3-carbaldehyde (2) using standard conditions of the Vilsmeier Haack reaction. Benzoyl glycine was reacted with 2 (step 2) followed by treatment with aromatic/aliphatic amines (step 3) to furnish the indolyl-imidazolone hybrids. In vivo anti-inflammatory and analgesic activity along with ulcerogenicity of the prepared hybrids were evaluated in experimental animals. Molecular properties and pharmacokinetic profile were also predicted using online computational software. Cyclooxygenase-2 (COX-2) enzyme (PDB: 3pgh) was used for molecular docking studies. Indomethacin and aspirin were used as reference compounds for the comparison purpose. ResultsThe percentage inhibition in edema in rats and reduction in frequency of acetic acid induced writhes in mice indicated that two compounds namely 3-(3-Hydroxpropyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl)methylene]-4H-imidazol-4-one (4g) and 3-(2,4-Dinitrophenyl)-2-phenyl-5-[(2-phenyl-1H-indol-3-yl) methylene]- 4H-imidazol-4-one (4b) could be useful in treating pain and inflammatory conditions. Both the hybrid molecules exhibited better biological spectrum than the standard drug indomethacin. Additionally, both the potent compounds were noted to be less ulcerogenic than indomethacin. Pharmacokinetic profile predicted using ADMETsar and SwissADME cheminformatic software indicated compound 4g to be orally bioavailable with high blood brain barrier permeability. However, molecular docking studies revealed that compound 4b binds to COX-2 enzyme more strongly than 4g as indicated by a lower binding energy and formation of hydrogen bond interactions with amino acid residues in the binding pocket. ConclusionsIt could be concluded that hybrid compounds 4b and 4g are promising lead candidates and should be further studied to develop compounds for the treatment of inflammatory conditions.

A simple validated HPTLC method for the analysis of flavonoids and molecular docking studies of novel tri-terpenoid glycoside isolated from Carya illinoinensis bark with potential anti-inflammatory and antinociceptive activities

Carya illinoinensis (Family Juglandaceae) is frequently used in traditional medicine for its antimicrobial, antioxidant, anti-rheumatic, anti-diabetic, and diuretic activities. Column chromatography was used to separate phytoconstituents from an ethanolic extract of powered bark. The terpenoid glycosidic compound, CI-01, was isolated as light-yellow crystalline powder in 0.33% (w/w) yield having melting point 94–96 °C, RF value 0.57 (in MeOH:CHCl3;20:80), UV absorption maxima 242 nm in methanol and molecular ion [M + H]+ peak at 420.4 m/z. Based on high-performance thin-layer chromatography and spectral data, the isolated compound CI-01, was identified as Farnesoic acid -l-glucoside. The ethanolic extract of Carya illinoinensis (CIE) at doses of 100 and 200 mg/kg and isolated compound CI-01 at 10 mg/kg dose were used for studying anti-inflammatory and antinociceptive effects. After 5 h of treatment with CI-01, the mean increase in paw volume was 0.459 ± 0.054 ml, which is corresponding to the standard drug indomethacin's 0.443 ± 0.041 ml. However, CIE groups receiving 100 and 200 mg/kg exhibited 0.518 ± 0.068 and 0.486 ± 0.048 ml, respectively. Compared to the control group of mice, animals treated with CIE and CI-01 dramatically reduced the number of writhes caused by acetic acid. AutoDock Vina program was used for molecular docking of the compound CI-01 with various targets, including COX-1, COX-2, inducible nitric oxide synthase, tumor necrosis factor-α, and opioid receptors exhibiting mean binding energies of -5.36, -7.37, -7.24, -4.27, and -7.04 kcal/mol, respectively. In conclusion, CI-01, isolated from Carya illinoinensis extract, demonstrated anti-inflammatory and antinociceptive activities at a dose of 10 mg/kg and displayed promising interaction with COX-2 in molecular docking study.

Antinociceptive Activity of Syzygium Aromaticum Linn. Flower Buds (Clove) Extract and its Fractions

Syzygium aromaticum (Myrtaceae) flower buds (clove) are traditionally known to possess antimicrobial, antiprotozoal, antiviral and other activities, including the antinociceptive action. Scientific evidence also suggests the antileishmanial, antiherpetic and anti-HIV activities of the buds. This paper reports the antinociceptive activity of S. aromaticum flower buds, reinforcing its use in decreasing the pain. The present study was designed to confirm the analgesic activity of S. aromaticum extract and seven of its fractions to reveal the common belief in its painkilling effects. We chose two thermal nociception assays (i) hot–plate test (ii) and tail-flick method as our experimental techniques. Both of these methods are well established to screen anti-nociceptive activities in new molecules. The standard drug indomethacin (5 mg/kg) given by intra-peritoneal route was used in the study for comparison. The study has shown that the methanolic extract (SA-EXT) and its active fractions possess anti-nociceptive activity (pandlt;0.05) in the models of nociception used.

Anti-Inflammatory and Analgesic Evaluation of Parinari curatellifolia Methanol Leaf Extract on Albino Rats

Aim: This research was designed to evaluate the anti-inflammatory and analgesic activities of Parinari curatellifolia methanol leaf extract in albino rats.&#x0D; Methodology: Phytochemical screening was carried out using standard methods. Anti-inflammatory activity of the extract was done using egg albumin and formalin induced hind paw edema model. Analgesic effect was evaluated using hot plate induced pain and acetic acid induced writhing test. For each model twenty (20) rats were used, divided into five (5) groups of four (4) rats each.&#x0D; Results: Parinari curatellifolia revealed the presence of alkaloids, flavonoids, tannins and phenols while steroids, anthraquinone, terpenoids and glycoside were not detected. For the egg albumin induced inflammation, the group treated with the standard drug (indomethacin) and the group that received the highest dose of the extract were significantly lower (P&lt;0.05) than all the other groups with percentage inhibitions at 25.56% and 24.44% respectively there was no significant difference (P&gt;0.05). For the formalin induced anti-inflammatory activity, at the 1st hour, the normal control group had its paw volume significantly different (P&lt;0.05) from the treated groups. This trend was observed at the 2nd, 3rd and 4th hour. The hot plate method results revealed significant increased (P&lt;0.05) in the analgesic activity of PCMLE at 400mg/kg body weight and the drug treated group when the control was compared with the treated groups with percentage inhibition of 34.32% and 52.94% respectively. The acetic acid induced writhing test revealed that the extract at the three doses of 100, 200 and 400 mg/kg body weight, showed a significant (P&lt;0.05) percentage inhibition of 32.31%, 36.92% and 47.69%, respectively compared to negative control.&#x0D; Conclusion: This justifies the use of Parinari curatellifolia locally in the management of pain and inflammation.