{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:36:52Z","timestamp":1760240212004,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T00:00:00Z","timestamp":1554422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical University-Plovdiv, Bulgaria","award":["NO-7\/2015"],"award-info":[{"award-number":["NO-7\/2015"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and objectives: The clinical use of non-steroidal anti-inflammatory drugs is limited due to high incidence of adverse drug reactions. The pyrrole heterocycle is included in the chemical structure of a number of drugs with various activities and shows relatively good tolerability and safety. The objectives of our study were to evaluate the analgesic and anti-inflammatory activity, as well as possible organ toxicity, of 2-[3-acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid (compound 3g), a novel N-pyrrolylcarboxylic acid structurally similar to celecoxib. Materials and methods: All experiments were performed on 6-week-old male Wistar rats divided into parallel groups (n = 8). Antinociception was assessed using animal pain models with thermal and chemical stimuli (paw withdrawal, tail-flick, and formalin tests). Criteria for the analgesic effect were increased latency in the paw withdrawal and tail-flick tests and decreased paw licking time in the formalin test compared to animals treated with saline (control). Anti-inflammatory activity was measured using a carrageenan-induced paw edema model; the criterion for anti-inflammatory effect was decreased edema compared to control. Blood samples were obtained after animals were sacrificed to assess possible organ toxicity. Statistical analysis was performed with IBM SPSS 20.0. Results: 2-[3-Acetyl-5-(4-chloro-phenyl)-2-methyl-pyrrol-1-yl]-3-(1H-indol-3-yl)-propionic acid had analgesic action against chemical stimulus after single and multiple administration and against thermal stimulus after single administration. Compound 3g significantly suppressed carrageenan-induced paw edema after both single and continuous administration. After continuous administration, hematological tests showed that compound 3g decreased leukocyte and platelet levels and elevated serum creatinine levels. Conclusions: Antinociception with the tested compound is most likely mediated by spinal, peripheral, and anti-inflammatory mechanisms. Possible tolerance of the analgesic action at the spinal level develops after continuous administration. Anti-inflammatory activity is significant and probably the leading cause of antinociception. After multiple administration, compound 3g showed signs of potential nephrotoxicity and antiplatelet activity, as well as suppression of leukocyte levels.<\/jats:p>","DOI":"10.3390\/medicina55040093","type":"journal-article","created":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T11:36:01Z","timestamp":1554464161000},"page":"93","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Biological Screening of Novel Structural Analog of Celecoxib as Potential Anti-Inflammatory and Analgesic Agent"],"prefix":"10.3390","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2555-4600","authenticated-orcid":false,"given":"Hristina","family":"Zlatanova","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislava","family":"Vladimirova","sequence":"additional","affiliation":[{"name":"Department of Organic Synthesis and Fuels, Faculty of Chemical Technologies, University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilia","family":"Kostadinov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-5688","authenticated-orcid":false,"given":"Delian","family":"Delev","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya","family":"Deneva","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Faculty of Pharmacy, Medical University Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivanka","family":"Kostadinova","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University Plovdiv, 4002 Plovdiv, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.anclin.2011.04.009","article-title":"Challenges in acute pain management","volume":"29","author":"Gandhi","year":"2011","journal-title":"Anesthesiol. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.smim.2015.05.004","article-title":"Gaseous mediators in resolution of inflammation","volume":"27","author":"Wallace","year":"2015","journal-title":"Semin. Immunol."},{"key":"ref_3","unstructured":"McMahon, S.B., Koltzenburg, M., Tracey, I., and Turk, D. (2013). Inflammatory mediators and modulators of pain. Wall and Melzack\u2019s Textbook of Pain, Saunders Elsevier Inc.. [6th ed.]."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.iac.2012.12.002","article-title":"NSAID single-drug-induced reactions","volume":"33","author":"Woessner","year":"2013","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.giec.2011.07.003","article-title":"Epidemiology and role of nonsteroidal antiinflammatory drugs in causing gastrointestinal bleeding","volume":"11","author":"Lee","year":"2011","journal-title":"Gastrointest. Endosc. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.cld.2013.07.009","article-title":"Nonsteroidal anti-inflammatory drug\u2013induced hepatoxicity","volume":"17","author":"Unzueta","year":"2013","journal-title":"Clin. Liver Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.pop.2014.09.001","article-title":"Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys","volume":"41","author":"Rahman","year":"2014","journal-title":"Prim. Care Clin. Office Pract."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1517\/17425255.2014.856881","article-title":"Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity","volume":"10","author":"Singh","year":"2014","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1016\/j.tcm.2015.03.006","article-title":"Elevation of cardiovascular risk by non-steroidal anti-inflammatory drugs","volume":"25","author":"Anwar","year":"2015","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_10","unstructured":"McMahon, S.B., Koltzenburg, M., Tracey, I., and Turk, D. (2013). Analgesic drugs in development. Wall and Melzack\u2019s Textbook of Pain, Saunders Elsevier Inc.. [6th ed.]."},{"key":"ref_11","first-page":"582","article-title":"Synthesis, characterization and biological activities of novel substituted formazans of 3,4-dimethyl-1Hpyrrole-2-carbohydrazide derivatives","volume":"7","author":"Bhosale","year":"2013","journal-title":"J. Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.bmcl.2014.12.040","article-title":"Design and synthesis of novel carbazole tethered pyrrole derivatives as potent inhibitors of Mycobacterium tuberculosis","volume":"25","author":"Surineni","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.ejmech.2014.01.021","article-title":"Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors","volume":"75","author":"Ji","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/0040-4039(95)00016-6","article-title":"1-Alkyl-3-(1-naphthoyl) pyrroles: A new class of cannabinoid","volume":"36","author":"Lainton","year":"1995","journal-title":"Tetrahedron Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1016\/j.ejmech.2010.03.028","article-title":"Synthesis and biological evaluation of some thio containing pyrrolo [2,3-d] pyrimidine derivatives for their anti-inflammatory and anti-microbial activities","volume":"45","author":"Mohamed","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1016\/j.ejmech.2011.04.034","article-title":"New condensed pyrroles of potential biological interest. Syntheses and structure-activity relationship studies","volume":"46","author":"Mohamed","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1016\/j.bmcl.2014.02.074","article-title":"Synthesis, biological evaluation, and docking analysis of a novel family of 1-methyl-1H-pyrrole-2,5-diones as highly potent and selective cyclooxygenase-2 (COX-2) inhibitors","volume":"24","author":"Kim","year":"2014","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_18","first-page":"434","article-title":"Anticonvulsant, analgesic and anti-inflammatory activities of some novel pyrrole and 1,4-dihydropyridine derivatives","volume":"7","author":"Indumathi","year":"2015","journal-title":"J. Chem. Pharm. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1515\/hc-2014-0022","article-title":"An access to new N-pyrrolylcarboxylic acids as potential COX-2 inhibitors via Paal-Knorr cyclization","volume":"20","author":"Vladimirova","year":"2014","journal-title":"Heterocycl. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.jpain.2013.06.008","article-title":"An overview of animal models of pain: Disease models and outcome measures","volume":"14","author":"Gregory","year":"2013","journal-title":"J. Pain"},{"key":"ref_21","first-page":"597","article-title":"Animal models of nociception","volume":"53","author":"Gozariu","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuroscience.2011.12.041","article-title":"Tests and models of nociception and pain in rodents","volume":"211","author":"Barrot","year":"2012","journal-title":"Neuroscience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0378-8741(01)00194-5","article-title":"Potent anti-inflammatory activities of hydroalcoholic extract from aerial parts of Stachys inflata on rats","volume":"75","author":"Maleki","year":"2001","journal-title":"J. Ethnopharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0928-0987(97)10020-3","article-title":"Evaluation of the formalin test to assess the analgesic activity of diflunisal in the rat","volume":"6","author":"Meunier","year":"1998","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jtcme.2014.11.038","article-title":"Evaluation of the anti-inflammatory activity of the aqueous and ethanolic extracts of the leaves of Albizzia lebbeck in rats","volume":"6","author":"Meshram","year":"2016","journal-title":"J. Tradit. Complement. Med."},{"key":"ref_26","first-page":"115","article-title":"Carrageenan-induced paw edema in the rat and mouse","volume":"225","author":"Morris","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1002\/ardp.200500191","article-title":"Further evaluation of a series of anti-inflammatory N-pyrrolylcarboxylic acids: Effects on the nociception in rats","volume":"339","author":"Bocheva","year":"2006","journal-title":"Arch. Pharm."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1111\/j.1600-0773.1998.tb01478.x","article-title":"Aspects on tail-flick, hot plate and electrical stimulation tests for morphine antinociception","volume":"83","year":"1998","journal-title":"Pharmacol. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3389\/fnins.2011.00092","article-title":"Tolerance to non-opioid analgesics is opioid sensitive in the nucleus raphe magnus","volume":"5","author":"Tsagareli","year":"2011","journal-title":"Front. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1080\/13102818.2014.932136","article-title":"Study on anti-inflammatory and immunomodulatory effects of clomipramine in carrageenan- and lipopolysachharide-induced rat models of inflammation","volume":"28","author":"Kostadinov","year":"2014","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_31","first-page":"6108203","article-title":"In vivo evaluation of the anti-inflammatory effect of Pistacia lentiscus fruit oil and its effects on oxidative stress","volume":"2016","author":"Khedir","year":"2016","journal-title":"Evid. Based Complement. Alt. Med."},{"key":"ref_32","unstructured":"(2016, June 16). Drug Monograph Celecoxib. Available online: https:\/\/www.clinicalkey.com\/#!\/content\/drug_monograph\/6-s2.0-689."},{"key":"ref_33","first-page":"1045","article-title":"A longitudinal study of serum creatinine levels in patients of rheumatoid arthritis on long term NSAID therapy","volume":"51","author":"Pathan","year":"2013","journal-title":"J. Assoc. Phys. India"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/00000441-199305000-00011","article-title":"Case report: Hyponatremia associated with nonsteroidal anti-inflammatory drugs","volume":"305","author":"Rault","year":"1993","journal-title":"Am. J. Med. Sci."},{"key":"ref_35","first-page":"833","article-title":"Effect of two non-steroidal anti-inflammatory drugs, aspirin and nimesulide on the D-glucose transport and disaccharide hydrolases in the intestinal brush border membrane","volume":"57","author":"Sanyal","year":"2005","journal-title":"Pharmacol. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1080\/003655200750023156","article-title":"Comparison of the intestinal toxicity of celecoxib, a selective COX-2 inhibitor and indomethacin in the experimental rat","volume":"35","author":"Tibble","year":"2000","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.iac.2012.10.008","article-title":"Classification of reactions to nonsteroidal anti-inflammatory drugs","volume":"33","author":"Kowalski","year":"2013","journal-title":"Immunol. Allergy Clin. N. Am."},{"key":"ref_38","unstructured":"Benzon, H., Rathmell, J., Wu, C.L., Turk, D., Argoff, C., and Hurley, R. (2014). Nonsteroidal anti-inflammatory drugs, acetaminophen, and COX-2 inhibitors. Practical Management of Pain, Mosby Elsevier Inc.. [5th ed.]."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1177\/147323001003800419","article-title":"Update on the incidence of metamizole sodium-induced blood dyscrasias in Poland","volume":"38","author":"Basak","year":"2010","journal-title":"J. Int. Med. Res."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/4\/93\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:43:17Z","timestamp":1760186597000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/4\/93"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,5]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["medicina55040093"],"URL":"https:\/\/doi.org\/10.3390\/medicina55040093","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2019,4,5]]}}}