Significant Analgesic Activity Research Articles

Design, synthesis, and biological evaluation of novel imidazole derivatives as analgesic and anti-inflammatory agents: experimental and molecular docking insights

Imidazole moieties exhibit a broad range of biological activities, including analgesic, anti-depressant, anticancer, anti-fungal, anti-tubercular, anti-inflammatory, antimicrobial, antiviral, and antifungal properties. In this study, we explored the use of Schiff base for the synthesis of new imidazole derivatives as anti-inflammatory and pain-relieving agents. A series of eight novel imidazole analogues (2a–h) were prepared in three steps with excellent yields. All compounds were characterized using IR, NMR, and mass spectral data. Their analgesic and anti-inflammatory activities were evaluated using hot plate and paw oedema methods. Compound 2 g (1-(2,3-dichlorophenyl)-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole) showed significant analgesic activity (89% at 100 mg/kg b.w.), while compounds 2a (2-(2,6-dichlorophenyl)-1-(4-ethoxyphenyl)-4,5-diphenyl-1H-imidazole) and 2b (2-(2,3-dichlorophenyl)-1-(2-chlorophenyl)-4,5-diphenyl-1H-imidazole) exhibited good anti-inflammatory activity (100% at 100 mg/kg b.w.), comparable to diclofenac salt (100% at 50 mg/kg b.w.). Molecular docking studies were conducted using Schrödinger software version 2021-2, employing the OPLS4 force field for both receptor and ligand preparation. The results were visualized using molecular visualization software such as PyMOL. These studies revealed that compound 2g exhibited the highest binding affinity with the COX-2 receptor (−5.516 kcal/mol). Compound 2g formed three conventional hydrogen bonds with residues GLN-242 (bond length: 2.3 Å) and ARG-343 (bond lengths: 2.2 Å & 2.4 Å). This binding affinity was comparable to that of Diclofenac salt, which showed the highest binding affinity of −5.627 kcal/mol with the COX-2 receptor. Diclofenac salt formed two conventional hydrogen bonds with the residues ARG-344 (bond length: 2.0 Å) and TRP-140 (bond length: 1.7 Å). Later, molecular dynamic simulations confirmed the stable binding affinity of compound 2g with the protein. Furthermore, other compounds also demonstrated potential binding to the receptor-binding pocket region. The anti-inflammatory potential of the synthesized compounds was evaluated using the carrageenan-induced rat hind paw oedema model, while the analgesic potential was assessed using the hot plate method. These evaluations were conducted in comparison with Diclofenac sodium, serving as the standard compound. However, compound 2g stood out for its superior analgesic activity, as confirmed by in-vivo examination. These findings suggest that these novel imidazole derivatives have potential as anti-inflammatory and analgesic agents.

Biological and Photocatalytic Activities of Silver Nanoparticles Synthesized from the Leaf Extract of Euphorbia royleana Boiss.

Silver nanoparticles (AgNPs) have gained significance due to their practical use in the medicinal field, especially in the treatment of tumors and cancer. The current article explores a green synthetic method for the preparation of AgNPs using leaf extract of Euphorbia royleanas. The synthesis was conducted at different parameters like concentration of AgNO3, pH, salt concentration, temperature and time to optimize best results for their biochemical applications. It was validated through UV-V spectroscopy (400-450 nm) with 1:3 (concentration ratio of leaf ethanolic extract and 1 mM AgNO3 solution) at a pH value of 8 at 35oC, which were the best optimization conditions. The FTIR spectral bands showed the presence of C-N and -OH functional groups, indicating that -OH stretching and the aliphatic -C-H stretching were involved in the reduction of Ag ions. The XRD pattern showed the face-centered cubic structure of silver nanoparticles. The results of SEM revealed that AgNPs were predominantly spherical in shape, mono-dispersed, and arranged in scattered form. EDX analysis testified the presence of metallic silver along with other elements like Cl, C, and O. The investigation of biochemical parameters showed that AgNPs were influential in the discoloration of dye wastewater (methylene blue ), where 80% of dye color was removed in 20 min, followed by the significant (p < 0.05) analgesic activity with an inhibition percentage of 86.45% at a dose of 500 mg/kg. Similarly, the antioxidant activity with the highest percent inhibition was 55.4% (p < 0.0001), shown by the AgNPs at 500 μg/mL. AgNPs showed a 30 mm zone of inhibition at 100 μl/mL against Aspergillus niger. It was concluded that AgNPs provide a baseline in medical technology for the treatment of simple to chronic diseases.

Hybrid Analogues of Hydrazone and Phthalimide: Design, Synthesis, In vivo, In vitro, and In silico Evaluation as Analgesic Agents.

Based on the anti-inflammatory and analgesic activity of hydrazone and phthalimide, a new series of hybrid hydrazone and phthalimide pharmacophores was prepared and evaluated as analgesic agents. The designed ligands were synthesized by reaction of the appropriate aldehydes and 2- aminophthalimide. Analgesic, cyclooxygenase inhibitory, and cytostatic activity of prepared compounds were measured. All the tested ligands demonstrated significant analgesic activity. Moreover, compounds 3i and 3h were the most potent ligands in the formalin and writhing tests, respectively. Compounds 3g, 3j, and 3l were the most COX-2 selective ligands and ligand 3e was the most potent COX inhibitor with a 0.79 of COX-2 selectivity ratio. The presence of electron-withdrawing moieties with hydrogen bonding ability at the meta position was found to affect the selectivity efficiently, in which compounds 3g, 3l, and 3k showed high COX-2 selectivity, and compound 3k was the most potent one. The cytostatic activity of selected ligands demonstrated that compounds 3e, 3f, 3h, 3k, and 3m showed good analgesic and COX inhibitory activity and were less toxic than the reference drug. High therapeutic index of these ligands is one of the valuable advantages of these compounds.

Phytochemical Screening, Antioxidant, Cytotoxic, Analgesic, Antidiarrheal Activity and GC-MS Analysis of the Leaves of Stachyphrynium Placentarium

The goal of the present study is to analyze the phytochemicals, antioxidants, cytotoxic, analgesic and anti-diarrheal properties of the leaves of Stachyphrynium placentarium methanol extract as well as its dichloromethane soluble fraction using GC-MS technique. The leaves of the S. placentarium were extracted with methanol and designated as SPM. Phytochemicals investigation exhibited the presence of several important secondary metabolites. Antioxidants such as total phenolic content, flavonoids content, total antioxidant, reducing power capacity and DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay SPM revealed non-significant antioxidant properties. The cytotoxicity study of the extract showed significant cytotoxicity (LC50 35.1093 µg/mL) compared to standard vincristine sulfate (LC50 0.482 µg/mL). Analgesic study of S. placentarium by hot plate model indicates both the doses exhibited significant central analgesic activity compared with the control. The maximum analgesic activity was observed at 90 min. SPM (500 mg/kg) is 60.21 %. SPM250 also showed a significant percentage of elongation or latency from 30 to 150 min 57.00, 59.64, 59.88, 58.07 and 53.71 %, respectively 30 min time interval. In the acetic acid writhing test, S. placentarium significantly outperformed the control and standard (SPM250 - 52.27 %, SPM500 - 34.09 and STD - 27.27 %), showing a significant increase in peripheral analgesic activity (p &lt; 0.001). Antidiarrheal activity of SPM showed that SPM250 and SPM500 substantially decreased the feces in castor oil-induced diarrhea (p &lt; 0.05). According to the study, the incidence and severity of diarrhea are significantly reduced by SPM500. Four chemicals are found in the dichloromethane-soluble portion of the methanol extract of S. placentarium leaves, according to GC-MS studies such as Octadecane, 6-methyl- (1.326 %), Dodecane (1.02 %), 1-Iodo-2-methylundecane (0.47 %), tetradecanoic acid 12-methyl, methyl ester (72.64 %). Tetradecanoic acid exhibits anti-inflammatory, anticancer, 5-reductase inhibitory, antioxidant, hemolytic and antifibrinolytic properties. HIGHLIGHTS The phytochemicals, antioxidants, cytotoxic, analgesic and anti-diarrheal properties of Stachyphrynium placentarium methanol extract (SPM) leaves. The dichloromethane soluble fraction is examined using Gas chromatography–mass spectrometry (GC-MS) and identified Octadecane, 6-methyl-, Dodecane, 1-Iodo-2-methylundecane, tetradecanoic acid 12-methyl, methyl ester. The brine shrimp lethality test exhibited that SPM has significant cytotoxicity (LC50 35.1093 µg/mL) compared to vincristine sulphate (LC50 0.482µg/mL), the extract showed significant cytotoxicity (LC50 35.1093 µg/mL). S. placentarium at both dosages (250 and 500 mg) provided significant central analgesia compared to the control in a hot plate model. In the acetic acid writhing test, S. placentarium showed significantly higher peripheral analgesic action (SPM250 - 52.27, SPM500 - 34.09 and STD - 27.27 %) compared to control and standard. In castor oil-induced diarrhoea, SPM250 and SPM500 (250 and 500 mg) showed significantly reduced faeces production (p &lt; 0.05). GRAPHICAL ABSTRACT

Anti-Inflammatory, Antinociceptive, and LC-MS Metabolic Profile from Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil.

Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil (Iridaceae) is a popularly known species with primarily ornamental economic interest. It has traditional uses as purgative, in conditions related to the menstrual cycle, for blood purification, as wound healing, and as anti-inflammatory. The anti-inflammatory and antinociceptive activities of the decoction from its aerial stems, corms, and stamens are described here with dereplication studies on LC-MS/MS supported by the GNPS platform, where phenolic compounds were annotated and correlated with its biological activity. The decoction was evaluated in chemical (formalin and capsaicin) and thermal (hot plate) induced nociception or carrageenan-induced inflammation in mice. Decoction (at 10, 30, or 100 mg/kg doses) significantly reduced formalin- or capsaicin-induced nociception. All doses also demonstrated an antinociceptive effect in the hot plate model increasing the time the animal spent in responding to thermal signal. Naloxone partially reversed the antinociceptive effect. An anti-inflammatory effect was observed since a reduction in cell migration, protein extravasation interleukin-1, and tumor necrosis factor production induced by carrageenan in the subcutaneous air pouch was quantified. Metabolomic analyses showed a predominance of phenolic substances, mainly flavonoids and chlorogenic acids. The literature showed that these two groups have significant anti-inflammatory and analgesic activity, and chemical data corroborate the pharmacological results observed.

To Evaluate and Compare the Analgesic Activity of Piperine and Extracts of Piper Nigrum L. Fruit

Narcotics (e.g., opioids) or non-narcotics (e.g., salicylates and corticosteroids) are used in the management of pain and inflammation, both of which have side effects, thereby emphasizing the search for natural substances. Piperine found naturally in plants of the Piperaceae family has shown inhibitory activity against 5-lipoxygenase and cycloxygenase-1 in in vitro studies. The present study was aimed to evaluate and compare the analgesic activity of pure compound, piperine along with hexane and ethanol extracts of Piper nigrum L. fruit in mice. The analgesic activity was determined by hot plate, tail immersion method and acetic acid induced writhing test in mice. The piperine showed great pain-relieving impact at a portion of 5 and 10 mg/kg when contrasted with control and standard. Greatest pain-relieving impact was noted at a portion of 10 mg/kg after 120 min. The hexane and ethanol remove demonstrated helpless pain-relieving impact at all dosages (5, 10 and 20 mg/kg) by hot plate method. However, with tail immersion method, piperine at a dose of 5mg/kg and ethanol extract at a dose of 20mg/kg after 120 min and hexane extract at a dose of 10mg/kg after 60min exhibited significant analgesic activity. In writhing test ethanol extract significantly stopped the number of writhes at dose of 20mg/kg while piperine at dose of 20mg/kg completely terminated the writhes in mice. It is concluded from the present study that Piper nigrum L. possesses potent analgesic activity in mice. Keywords: Piper nigrum, Piperaceae, Piperine, Hot plate, Tail immersion method, Acetic acid induced writhing test

Assessing Therapeutic Potentials of Catharanthus roseus (L.) G. Don Focusing on Anti-Diabetic, Analgesic and Anti-Diarrheal Activities

Catharanthus roseus, or 'Nayantara' in Bengali, is a perennial flowering herb. This study aimed to evaluate the pharmacological effectiveness of the plant, focusing on its anti-diabetic, peripheral and central analgesic, and antidiarrheal effects. Methanol soluble partition 200 (MSP-200) and 400 (MSP-400) mg/kg body weight were administered for glucose tolerance test (GTT), heat and chemical-induced response tests, sodium thiosulphate induced test, and castor oil induced test, evaluating anti-diabetic, peripheral and central analgesic, and antidiarrheal effects via in-vivo assay in Swiss-Albino mice model. Methanol soluble partition (MSP) at 200 and 400 mg/kg doses significantly reduced the blood glucose levels of mice by 31.00% and 32.97%, respectively (standard 46.24%). In peripheral analgesic activity, MSP-400 (62.82 ± 4.62%) outperformed MSP-200 (50 ± 3.62%) and MSP-200 (p = 0.0001) exhibited statistically significant central analgesic activity. MSP-400 demonstrated potent anti-diarrheal activity (p = 0.0002). The outcomes from this study put forward a cogent argument that C. roseus plant is capable of producing numerous bioactive compounds such as flavonoids, alkaloids, terpenoids, tannins, etc. which requires systematic phytochemical and pharmacological investigations. Bangladesh Pharmaceutical Journal 27(2): 215-222, 2024 (July)

Synthesis, characterization, and molecular docking studies of novel hippuric acid anhydrides as potential antiurolithic, analgesic and free radical scavenging agents

Hippuric acid is a biotransformation product in humans which is excreted through urine. Dietary intake of phenolic compounds increases its concentration in urine. Hippuric acid is experimentally proved to be a regulator of calcium oxalate super saturation in human urine and has a solvent effect on oxalate salts. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used analgesics employed in associated renal colic of urolithiasis. The objective of the present study was to chemically link hippuric acid through anhydride linkage to various NSAIDs to synthesize potential mutual prodrugs for urolithiasis and associated renal colic. Hippuric acid was linked to eleven NSAIDs through anhydride linkage by first synthesizing hippuryl chloride using oxalyl chloride as chlorinating agent, followed by its reaction with sodium salts of NSAIDs. Structures of obtained compounds were elucidated using UV spectrophotometry, FTIR spectrometry, 1H NMR and C-13 NMR spectrometry. Synthesized compounds were evaluated for in vitro antioxidant, in vivo acute toxicity, in vivo antiurolithic, in vivo analgesic and in vitro hydrolysis studies. Molecular docking analysis on TNF-α and COX-2 was carried out to determine target protein binding. Synthesized compounds showed stability at acidic pH which indicate potential gastro protective effect of synthesized conjugates. Compounds P9 an P6 showed maximum in vivo antiurolithic activity while P9 and P8 showed maximum in vitro antioxidant activity. All the conjugates except P2 showed significant analgesic activity which show that conjugation of hippuric acid to NSAIDs did not result in loss of analgesic potential. Docking studies showed better affinity with TNF-α as compared to COX-2.

Analgesic and anti-inflammatory activities of NPK 500 capsules, a Cassia sieberiana DC. - Based herbal analgesic medicine used to treat dysmenorrhea and peptic ulcer, is mediated through the inhibition of PGE2 and iNOS

Ethnopharmacological relevancePain and inflammation are the most frequent reasons for which people seek medical care. Currently available analgesics against these conditions produce fatal adverse effects. NPK 500 capsules is an alternative herbal analgesic employed to treat dysmenorrhea, peptic ulcer and pain. NPK 500 is produced from Cassia sieberiana. A plant used in traditional medicine to treat pain and inflammation. Aim of the studyThis study reports the analysis, phytochemical characterization and mechanism of analgesic and anti-inflammatory activities of two NPK 500 capsules, called old and new NPK500 capsules (ONPK500 and NNPK500) respectively. Materials and methodsPhysicochemical, organoleptic, GC-MS and LC-MS methods were employed to analyze the NPK 500 capsules. Analgesic activity was evaluated using tail immersion, Randall-Selitto and acetic acid induced writing tests. Anti-inflammatory activity was evaluated using carrageenan-induced rat paw inflammation. Additionally, pro-inflammatory mediators such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase 1 and 2 (COX-2 and COX-1) were quantified in the sera of the rats using Enzyme Linked Immunosorbent Assay (ELISA) kits. ResultsThirteen major compounds were characterized in the NNPK 500 capsules via the GC-MS and LC-MS spectroscopies. Kaempferol was the major compound characterized in addition to physcion, β-sitosterol 3-O-β-D-glucopyranoside, betulinic acid and nine others. Physicochemical and organoleptic indices of the capsules were also derived for its authentication and quality control. Furthermore, NNPK 500 0.5–1.5 mg/kg p.o. produce significant (P < 0.5) analgesic activity (160–197%) higher than that of ONPK500 (109.8%) and Morphine (101%) in the tail immersion test. The analgesic activity of NNPK 500 0.5–1.5 mg/kg p.o. (171.0–258.3%) and ONPK 500 (179.5%) were also significant (P < 0.01) and higher than that of Aspirin (103.00%) in the Randall-Selitto test. Both capsules also demonstrated significant (P < 0.5) analgesic and anti-inflammatory activities in the acetic acid-induced writhing and carrageenan-indued paw edema tests respectively. The two NPK500 capsules also, significantly (P < 0.5) inhibited PGE2 and iNOS but not COX-2 and COX-1 in the carrageenan-indued paw edema test. ConclusionThese results show that NNPK 500 and ONPK 500 capsules possessed potent analgesic and anti-inflammatory activities via inhibition of PGE2 and iNOS as a result of their chemical constituents. NPK500 capsules thus, relief acute pain and inflammation without causing gastrointestinal, renal or hepatic injuries, since they did not inhibit COX-1.

Pharmacological, Phytochemical and Computational Studies on Prenylated Flavonoids and Pterocarpans From Erythrina Fusca Lour.

In the present study, the dry powdered bark of Erythrina fusca was extracted with methanol. It was subjected to peripheral analgesic study using the acetic acid-induced writhing test in mice model and it demonstrated significant analgesic activity. The methanol extract was partitioned into n-hexane, chloroform and water-soluble fractions. Primarily, the chloroform fraction of the methanol extract was subjected to various chromatographic techniques and four major metabolites, Lupinifolin (1), Lupinifolin-4’-methyl ether (2), Sandwicensin (3) and Licoagrocarpin (4) were purified. Molecular docking studies of 1-4 against cyclooxygenase-2 (COX-2) enzyme suggest that they may interact with COX-2 at different levels. The pharmacokinetic and biological parameters of 1-4 were also checked through in silico tool to understand their drug-likeliness. Bangladesh J. Bot. 53(2): 305-311, 2024 (June)

Evaluation of anti-nociceptive and anti-inflammatory activities of solvent fraction of the roots of Echinops kebericho Mesfin (Asteraceae) in mice model.

The present study was aimed at investigating the antinociceptive and anti-inflammatory activities of the solvent fractions of the roots ofEchinops keberichoMesfin in rodent models of pain and inflammation. Successive maceration was used as a method of extraction using solvents of increasing polarity: methanol and water. Ethyl acetate, chloroform and distilled water were used as solvents of the fraction process. Swiss albino mice models were used in acetic acid induced writhing, hot plate, carrageenan induced paw edema and cotton pellet granuloma to assess the analgesic and anti-inflammatory activities. The test groups received different doses (100 mg/kg, 200 mg/kg and 400 mg/kg) of the three fractions (chloroform, ethyl acetate and aqueous). The positive control groups received ASA (150 mg/kg) for the writing test, morphine (10 mg/kg) for the hot plate method, diclofenac Na for carrageenan-induced paw edema, and dexamethasone (10 mg/kg) for granuloma, while the negative control group received distilled water. EA fraction at all test doses employed (100 mg/kg, 200 mg/kg, and 400 mg/kg) showed statistically significant (p<0.05, p<0.01, p<0.001 respectively) analgesic and anti-inflammatory activities in a dose-dependent manner. The AQ fraction on the other hand produced statistically significant (p<0.05, p<0.012) analgesic and anti-inflammatory activities at the doses of 200 mg/kg and 400 mg/kg, while the CH fraction exhibited statistically significant (p<0.05) analgesic and anti-inflammatory activity at the dose of 400 mg/kg. In general, the data obtained from the present study elucidated that the solvent fractions of the study plant possessed significant analgesic and anti-inflammatory activities and were recommended for further investigations.

Phytochemical Screening, GC-MS Analysis, and Evaluation of Antioxidants, Cytotoxicity, Analgesic, and Anti-Diarrheal Activity of the Extracts of the Leaves of Syzygium reticulatum Wight Walp

Syzygium genus is extensively used in managing different diseases such as antimicrobial, anti-diarrheal, antidiabetic, analgesic, anti-inflammatory, antioxidant, and anticancer activities. The present study aims to investigate phytochemicals by screening tests and GC-MS analysis and evaluate the antioxidants, cytotoxicity, analgesic, and anti-diarrheal activity of the extracts of the leaves of Syzygium reticulatum. The leaves of the S. reticulatum were extracted with hexane and methanol by the maceration process successively, denoted as SRH and SRM. The extract’s phytochemical analyses found flavonoids, alkaloids, saponins, tannins, glycosides, and carbohydrates. The GC-MS analysis of the methanol extract identified 8 compounds. The major components were identified as Diisooctyl phthalate (96.903 %), 2-methyltetracosane (1.094 %), and others with fewer amounts. The result of the antioxidant study of the extracts as total phenolic content of SRH 8.92 ± 0.62 and SRM 340.107 ± 11.11 mg/g, respectively, total flavonoids content of SRH 7.85 ± 0.71 and SRM 105.16 ± 0.93 mg/g, IC50 values of the DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical scavenging assay of SRM was 14.67 µg/mL, SRH was 41.26 µg/mL and ascorbic acid 14.08 µg/mL; the total antioxidant capacity of SRH was 21.33 ± 2.52 mg/g, whereas SRM was 353.71 ± 4.59 mg/g. The results of these studies suggest that methanol extract has a more potent antioxidant capacity than hexane extract. The methanol extract also exhibited higher toxicity (LC50 value 49.99 µg/mL) compared to hexane extract (LC50 value 370.348 µg/mL), as revealed by the Brine shrimp nauplii cytotoxic study. An analgesic study of the methanol extract found that a lower dose (250 mg/kg) has more significant analgesic activity than the higher dose and standard drug aspirin. At 90 min, the hot plate’s highest percentage of latency elongation was 110.32, while the acetic acid-induced writhing inhibition was 63.04 %. At a dose of 500 mg/kg, the methanol extract also shown good efficacy in mice suffering from castor oil and magnesium sulfate-induced diarrhea. The findings from the study of the leaves of the S. reticulatum exhibited that methanol extracts have significant antioxidant, cytotoxic, analgesic, and anti-diarrheal activity. HIGHLIGHTS The extract’s phytochemical analyses found flavonoids, alkaloids, saponins, tannins, glycosides, and carbohydrates The GC-MS analysis of the methanol extract identified 8 compounds. The major components were identified as Diisooctyl phthalate (96.903 %), 2-methyltetracosane (1.094 %) The antioxidant and cytotoxicity studies suggest that methanol extract has a more potent antioxidant and cytotoxic capacity than hexane extract The findings from in-vivo study of the leaves of the reticulatum also exhibited that methanol extracts have significant analgesic, and anti-diarrheal activity GRAPHICAL ABSTRACT

Screening for Antinociceptive Action of Gastroretentive Drug delivery System of Tramadol hydrochloride in Mice

The floating drug delivery system is to avoid the problem of drug waste and to limit the frequency of administration. Here the drug Tramadol is being centrally acting opioid analgesic can be formulated as sustained release formulation by adopting the method gastroretentive drug delivery system through effervescent floating drug delivery system with different grades of polymer Hyperomellose. The Pharmacological activity on Mice by both Hot Plate and Tail Flick Methods also suggest that when the Tramadol Hcl increased with its dosage form shows significant Analgesic Activity in animals which shows a spontaneous dose dependent increase in Analgesic activity was found it shows that the dosage form deserve for designed method of gastroretentive drug delivery system.

Synthesis and biological evaluation of some novel benzoxazin-4-one and quinazolin-4-one derivatives based on anti-inflammatory commercial drugs

Benzoxazine and quinazoline are nitrogen-containing heterocyclic scaffolds found in various biologically active compounds. Due to their diverse biological actions, these heterocyclic rings serve as crucial frameworks for designing medicinal compounds. This study aimed to synthesize and assess in vivo anti-inflammatory, analgesic, and low ulcerogenic potential of a few novel benz[d][1,3]-oxazin-4-one and quinazolinone derivatives. Benzoxazinones (3a-e) were synthesized by cyclizing the carboxylic group (-COOH) of five nonsteroidal anti-inflammatory drugs viz., aceclofenac, ibuprofen, diclofenac, mefenamic acid and ketoprofen (2a-e) with anthranilic acid (1) using dry phosphorus oxychloride (POCl3) in pyridine. The corresponding quinazolinone derivatives (5a-e) were obtained by reacting 3a-e with isonicotinic acid hydrazide (4). Both sets of compounds were evaluated for their anti-inflammatory, analgesic effects, and ulcerogenicity in animal models. Structural characterization was performed using spectral analysis. Among the benzoxazinone derivatives, compound 2-(2-((2,6-dichlorophenyl) amino) benzyl)-4H-benzo[d][1,3]oxazin-4-one (3d) exhibited significant anti-inflammatory activity (62.61% inhibition of rat paw edema) and analgesic activity (62.36% protection in acetic acid-induced writhings) with tolerable gastrointestinal toxicity (2.67 ulcerogenicity index) compared to quinazolinone derivatives. The results of anti-inflammatory and analgesic activities of both the series are comparable with the respective, positive control. Compound 3d, a benzoxazinone-diclofenac hybrid, emerged as a lead molecule with potent anti-inflammatory, analgesic activities and moderate gastric toxicity showcasing the promising potential for further development.

Pharmacological screening of Anti-inflammatory and Analgesic activity of Apigenin in Mice Model

Introduction: Apigenin is a flavonoid found in many fruits and vegetables as well as in Chinese medicinal herbs. This study aimed to assess the anti-inflammatory and analgesic effects of Apigenin. Materials and Methods: Carrageenan-induced mouse paw edema was used to assess anti-inflammatory activityand Eddy's hot plate analgesiometer was used to assess analgesic activity. Results and Discussion: Apigenin at dosages of 25 mg/kg and 50mg/kg body weight significantly reduced Carrageenan-induced paw edema by 41.21% (3–9 h) and 61.4% (3–9 h), respectively. Apigenin 25mg/kg and 50mg/kg body weight produced significant dose-response analgesic activity in the hot plate test. Conclusion: The findings in this study suggest that Apigenin possesses anti-inflammatory and analgesic activities in a dose dependent manner.

Chemical Profiling and Biological Activities of Ziziphus Mauritiana var. spontanea (Edgew.) R.R. Stewart ex Qaiser &amp; Nazim. and Oenothera Biennis L.

Bioactive compounds of medicinal plants, including polyphenols, flavonoids, terpenoids, and alkaloids, are essential sources for developing analgesic, anti-inflammatory, and antidiarrheal drugs. In the current study, secondary metabolites were assessed through phytochemical screening and GC-MS analysis whereas analgesic activity was carried out through hot plate (HP) and acetic acid-induced method (AAI), anti-inflammatory through paw edema model (PEM), and antispasmodic activity via charcoal meal test (CMT) using ethyl acetate and ethanolic extract of Ziziphus mauritiana var. spontanea and Oenothera biennis. The phytochemical screening revealed that the ethyl acetate and ethanolic extracts of Z. mauritiana and O. biennis were rich in alkaloids, flavonoids, tannins, steroids, triterpenoids, and saponins. GC-MS analysis of Z. mauritiana and O. biennis of ethyl acetate and ethanolic extract showed the existence of many bioactive substances at various retention durations (min). These included pharmacologically active compounds such as heptadecane, 2-methoxy-4-vinylphenol, hexadecanoic acid, and tetradecanoic acid. The results of the HP method revealed that ethanolic and ethyl acetate extracts of Z. mauritiana and O. biennis at 300 mg/kg increased basal reaction time significantly (p&lt;0.001) after 90 min. The results of the AAI method revealed that the ethanolic and ethyl acetate extract of Z. mauritiana and O. biennis showed significant (p&lt;0.001) peripheral analgesic activity at the dose of 200 and 300 mg/kg body weight. The dosage of 100, 200, and 300 mg/kg body weight of the ethyl acetate and ethanolic extracts of Z. mauritiana and O. biennis showed significant (p&lt;0.001) anti-inflammatory activity. According to PEM, the ethanolic extract of O. biennis showed the highest reduction in paw volume (73.3%) at 300 mg/kg. The results of CMT revealed that ethanolic and ethyl acetate extract of Z. mauritiana and O. biennis significantly (p&lt;0.001) inhibited charcoal movement at 300 mg/kg. The maximum percent inhibition (67.2%) was shown by ethyl acetate of O. biennis at 300 mg/kg. From the present study, it can be concluded that ethanolic and ethyl acetate extracts of Z. mauritiana and O. biennis have the potential to manage inflammation, pain, and diarrhea-related problems mainly at a higher dose, i.e., 300 mg/kg. The presence of alkaloids, flavonoids, tannins, steroids, triterpenoids, and saponins might be among the responsible bioactive constituents. These plants showed significant medicinal and therapeutic efficacy which are novel. However, further studies are required to investigate the mechanism responsible for the activity.

Anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities of poly-fused ring pyrimidine derivatives

Purpose: To investigate the anti-inflammatory, anti-cancer, anti-parkinsonian, anti-microbial, analgesic, and anti-hyperglycemic properties of a variety of poly-fused pyrimidine derivatives.&#x0D; Methods: A novel series of fused pyrimidine derivatives 1-6 were synthesized by reacting amino pyrazole derivatives with active methylene derivatives to give the corresponding compounds 1-6. Anti-parkinsonian activity was investigated with benzotropene as a reference drug, anti-inflammatory effect in mice was evaluated using carrageenan in paw edema with indomethacin as reference drug, anti-microbial activity was assessed using nutritional agar with ciprofloxacin and ketoconazole as reference drugs, analgesic activity was evaluated using valdecoxib as reference drug, anti-hyperglycemic activity was investigated using alloxan and sucrose models (SLM) with pioglitazone as reference drug and anticancer activity was investigated using the MTT micro-cultured tetrazolium assay method with doxorubicin as reference drug.&#x0D; Results: Pyrimidine derivatives 1-6 possess significant active anti-parkinsonian, anti-inflammatory, anti-microbial, analgesic, anti-hyperglycemic and anticancer activities in comparison to the reference drugs used for each model. Compared to Benzotropene®, compounds 1 and 3 showed a significantly stronger anti-parkinsonian activity (p &lt; 0.03). Compound 3 showed a significantly stronger anti-inflammatory effect than Indomethacin® (p &lt; 0.05). Compounds 5 and 6 exhibited significant anti- microbial activity compared to ciprofloxacin® (p &lt; 0.05). Compounds 4 and 6 exhibited significantly improved analgesic activity as compared to Valdecoxib® (p &lt; 0.01). Compounds 1 and 3 exhibited significantly higher anti-hyperglycemic effects in SLM model when compared to pioglitazone® (p &lt; 0.02). Compound 5 demonstrated the highest activity against human colon cancer cell line (HT-29) and human prostate cancer cell line (DU145), and also, significantly improved level of efficacy against human lung cancer cell line (A549) compared to Doxorubicin® (p &lt; 0.02). &#x0D; Conclusion: Using the six pyrimidine derivatives 1 - 6 as a lead molecule, a novel class of clinically beneficial anti-cancer, anti-inflammatory, anti-microbial, analgesic, and anti-hyperglycemic drugs may be produced.

In-vivo Pharmacological Evaluation of Analgesic Activity of Ethanolic Extract of Doronicum hookeri Clarke Rhizomes in Wistar Rats

A number of plants are used traditionally in different medical conditions by practitioners of traditional medicines but their claim is not yet evaluated scientifically in laboratory animals. Based on the ethnomedical claims made by the Unani health practitioners, the Clarke rhizomes of Doronicum Hookeri was evaluated for analgesics activity in rats to confirm its claim. The successive plant extraction was carried out using Soxhlet apparatus by employing ethanol as a solvent of the dried rhizomes of Doronicum Hookeri. The % yield of extracted compound was 28.27% w/w. The qualitative preliminary phytochemical screening revealed the presence of alkaloids, saponins, tannins, flavonoids, glycosides, phenolic content, terpenoids and volatile oils in the rhizomes of ethanolic extract of D. Hookeri. The extract was orally administered in rats at low dose and high dose (200 mg/kg, 400 mg/kg) and was evaluated using Eddy’s Hot Plate Method in rats for analgesics activity. Diclofenac sodium (50 mg/kg) and was taken as a standard drug. The maximum possible analgesia % of ethanolic extract of rhizomes of D. Hookeri were found to be highest at a dose of 400mg/kg which showed 68.95% and 80% analgesia at 45 minute and 60 minute which when compared to Diclofenac sodium showed 73.28% and 85.71% at 45 minute and 60 minutes. The analgesic efficacy of ethanolic extract of rhizomes of D. Hookeri showed significant analgesic activity (p&lt;0.04) in dose dependent manner at different time intervals of 0, 15, 30, 45 and 60 min. This asserts ethnomedical claims of some tribes regarding the analgesic activity of this plant.&#x0D; Keywords - Analgesics, eddy’s hot plate, D. Hookeri, Diclofenac sodium.

Design and synthesis of novel dithiazole carboxylic acid Derivatives: In vivo and in silico investigation of their Anti-Inflammatory and analgesic effects

Inflammation is a complex set of interactions that can occur in tissues as the body's defensive response to infections, trauma, allergens, or toxic compounds. Therefore, in almost all diseases, it can be observed because of primary or secondary reasons.Since it is important to control and even eliminate the symptoms of inflammation in the treatment of many diseases, anti-inflammatory and analgesic drugs are always needed in the clinic. Therefore, the discovery of new anti-inflammatory/analgesic drugs with increased effectiveness and safer side effect profiles is among the popular topics of medicinal chemistry. Therefore, in this study, in order to synthesize and diversify new molecules, we focused on the N,N-dithiazole carboxylic acid core and linked it with the chalcone functional group.The final eleven molecules were analyzed via HRMS, 1H NMR, and 13C NMR. The antinociceptive effects of the test compounds were examined by tail-clip, hot-plate, and formalin methods in mice, while their anti-inflammatory activities were investigated by carrageenan-induced inflammation tests in rats. The motor activities of the experimental animals were evaluated using an activity-meter device. Obtained findings revealed that none of the test compounds (10 mg/kg) were effective in the tail-clip and hot-plate tests. However, compounds 4b, 4c, 4f, 4 h, and 4 k in the serial shortened the paw-licking times of mice in the late phase of the formalin test indicating that these compounds had peripherally-mediated antinociceptive effects. The same compounds, moreover, showed potent anti-inflammatory effects by significantly reducing paw edema of rats in the inflammation tests. To provide an approach to pharmacological findings regarding possible mechanisms of action, the binding modes of the most active compounds were investigated by in silico approaches. The results of molecular docking studies indicated that the anti-inflammatory and analgesic activities of the compounds might be related to the inhibition of both COX-1 and COX-2 isoenzymes. Findings obtained from in silico studies showed that 4 k, which was chosen as a model for its analogs in the series, forms strong bindings to the basic residues (Arg120, Tyr355), side pocket loop area and deep hydrophobic regions of the enzyme. Moreover, results of the molecular dynamics simulation studies revealed that ligand-COX enzyme complexes are quite stable. Obtained results of in vivo and in silico studies are in harmony, and all together point out that compounds 4b, 4c, 4f, 4 h, and 4 k have significant anti-inflammatory and analgesic activities with good ADME profiles.The potential of the derivatives, whose pharmacological activities were revealed for the first time in this study, as anti-inflammatory and analgesic drug candidates, needs to be evaluated through comprehensive clinical studies.

Novel endomorphin analogues CEMR-1 and CEMR-2 produce potent and long-lasting antinociception with a favourable side effect profile at the spinal level.

Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.