{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T18:45:49Z","timestamp":1786387549231,"version":"build-2736575974"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>\n                    In this study, we report the design and synthesis of a new series of pyrrolopyrimidine derivatives developed as dual-target nonsteroidal anti-inflammatory agents (NSAIDs). The compounds were evaluated for anti-inflammatory properties, cyclooxygenase-1\/2 (COX-1\/COX-2) inhibitory activity, and angiotensin-converting enzyme 2 (ACE2)\u2013blocking activity in lipopolysaccharide (lipopolysaccharide)-stimulated RAW264.7 cells. Among the synthesized molecules, compounds\n                    <jats:bold>5a<\/jats:bold>\n                    and\n                    <jats:bold>5b<\/jats:bold>\n                    showed potent dual inhibitory activity, which was supported by molecular docking and molecular dynamics simulations. These findings highlight the potential of selective COX-2 inhibitors with concurrent ACE2 blockade as a promising therapeutic approach for controlling inflammation and modulating pathways relevant to viral entry and other inflammation-associated disorders. While ACE2 inhibition has received particular attention in the context of recent viral infections, the broader anti-inflammatory efficacy of these derivatives supports their potential as multi-target drug candidates.\n                  <\/jats:p>","DOI":"10.3389\/fmolb.2025.1710650","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:19:50Z","timestamp":1767676790000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Pyrrolopyrimidine derivatives as dual COX-2\/ACE2 inhibitors: design, synthesis, and anti-inflammatory evaluation"],"prefix":"10.3389","volume":"12","author":[{"given":"Hala","family":"Afifi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar S.","family":"Fatahala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania H.","family":"Abd El-Hameed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahenda","family":"Mahgoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radwan","family":"El-Haggar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omnia","family":"Aly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal F.","family":"Gharib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira I.","family":"Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Taha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1080\/14756366.2021.1908277","article-title":"Utility of novel 2-furanones in synthesis of other heterocyclic compounds having anti-inflammatory activity with dual COX2\/LOX inhibition","volume":"36","author":"Abd El-Hameed","year":"2021","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B2","doi-asserted-by":"crossref","first-page":"719","DOI":"10.5012\/bkcs.2005.26.5.719","article-title":"Synthesis, reactions and antimicrobial activity of 2-Amino-4-(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile","volume":"26","author":"Abdel-Mohsen","year":"2005","journal-title":"Bull. Korean Chem. Soc."},{"key":"B3","doi-asserted-by":"publisher","first-page":"102025","DOI":"10.1016\/j.jsps.2024.102025","article-title":"Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer\u2019s agents","volume":"32","author":"Abdelazeem","year":"2024","journal-title":"Saudi Pharm. J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1007\/s40203-025-00407-4","article-title":"In-silico identification of COX-2 inhibitory phytochemicals from traditional medicinal plants: molecular docking, dynamics, and safety predictions","volume":"13","author":"Abdollahi","year":"2025","journal-title":"Silico Pharmacol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/ijms21155224","article-title":"Potential anti-covid-19 therapeutics that block the early stage of the viral life cycle: structures, mechanisms, and clinical trials","volume":"21","author":"Al-Horani","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.ijid.2020.09.1466","article-title":"COX2 inhibition in the treatment of COVID-19: Review of literature to propose repositioning of celecoxib for randomized controlled studies","volume":"101","author":"Baghaki","year":"2020","journal-title":"Int. J. Infect. Dis. IJID Off. Publ. Int. Soc. Infect. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.ejmech.2015.06.020","article-title":"Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2 H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents","volume":"101","author":"Banerjee","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-74715-4","article-title":"Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2","volume":"10","author":"Basu","year":"2020","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"3695","DOI":"10.1016\/j.bmc.2013.04.031","article-title":"A class of pyrrole derivatives endowed with analgesic\/anti-inflammatory activity","volume":"21","author":"Battilocchio","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"B10","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1007\/s10096-020-04138-6","article-title":"COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection","volume":"40","author":"Beyerstedt","year":"2021","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"B11","doi-asserted-by":"publisher","first-page":"114147","DOI":"10.1016\/j.bcp.2020.114147","article-title":"Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective","volume":"180","author":"Bindu","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"B12","doi-asserted-by":"publisher","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. Weinh."},{"key":"B13","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1136\/ard-2023-223850","article-title":"Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story","volume":"83","author":"Bonelli","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"6878","DOI":"10.4049\/jimmunol.175.10.6878","article-title":"Contrasting effects of cyclooxygenase-1 (COX-1) and COX-2 deficiency on the host response to influenza A viral infection","volume":"175","author":"Carey","year":"2005","journal-title":"J. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"39808","DOI":"10.1039\/d0ra08228g","article-title":"ACE2 as a potential therapeutic target for pandemic COVID-19","volume":"10","author":"Chatterjee","year":"2020","journal-title":"RSC Adv."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/molecules22111835","article-title":"Semisynthesis, an anti-inflammatory effect of derivatives of 1\u03b2-hydroxy alantolactone from inula britannica","volume":"22","author":"Chen","year":"2017","journal-title":"Molecules"},{"key":"B17","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.3390\/ijms19092729","article-title":"The cancer prevention, anti-inflammatory and anti-oxidation of bioactive phytochemicals targeting the TLR4 signaling pathway","volume":"19","author":"Chen","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e00014-21","DOI":"10.1128\/jvi.00014-21","article-title":"Nonsteroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection","volume":"95","author":"Chen","year":"2021","journal-title":"J. Virol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmed.2022.785785","article-title":"A home-treatment algorithm based on anti-inflammatory drugs to prevent hospitalization of patients with early COVID-19: a matched-cohort study (COVER 2)","volume":"9","author":"Consolaro","year":"2022","journal-title":"Front. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e370","DOI":"10.1016\/S1473-3099(22)00434-0","article-title":"The Johns Hopkins University Center for systems science and engineering COVID-19 dashboard: data collection process, challenges faced, and lessons learned","volume":"22","author":"Dong","year":"2022","journal-title":"Lancet. Infect. Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/1573406417666210304100830","article-title":"Synthesis of some novel benzimidazole derivatives as anticancer agent, and evaluation for CDK2 inhibition activity","volume":"17","author":"El-Hameed","year":"2021","journal-title":"Med. Chem. (Los. Angeles)"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12906-016-1301-z","article-title":"The anti-arthritic, anti-inflammatory, antioxidant activity and relationships with total phenolics and total flavonoids of nine South African plants used traditionally to treat arthritis","volume":"16","author":"Elisha","year":"2016","journal-title":"BMC Complement. Altern. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/molecules26123772","article-title":"Computational insights on the potential of some nsaids for treating covid-19: priority set and lead optimization","volume":"26","author":"Elmaaty","year":"2021","journal-title":"Molecules"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2895","DOI":"10.1021\/acs.jmedchem.7b01803","article-title":"Structure-activity relationship in monosaccharide-based toll-like receptor 4 (TLR4) antagonists","volume":"61","author":"Facchini","year":"2018","journal-title":"J. Med. Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"865","DOI":"10.17344\/acsi.2017.3481","article-title":"Synthesis and structure activity relationship of some indole derivatives as potential anti-inflammatory agents","volume":"64","author":"Fatahala","year":"","journal-title":"Acta Chim. Slov."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/molecules22030461","article-title":"Pyrrole and fused pyrrole compounds with bioactivity against inflammatory mediators","volume":"22","author":"Fatahala","year":"","journal-title":"Molecules"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/1871520617666170102152928","article-title":"Synthesis and evaluation of cytotoxic activity of some pyrroles and fused pyrroles","volume":"17","author":"Fatahala","year":"","journal-title":"Anticancer. Agents Med. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1080\/14756366.2018.1461854","article-title":"Synthesis and evaluation of novel spiro derivatives for pyrrolopyrimidines as anti-hyperglycemia promising compounds","volume":"33","author":"Fatahala","year":"2018","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.2174\/1573406418666220325141952","article-title":"Synthesis strategies and medicinal value of pyrrole and its fused heterocyclic compounds","volume":"18","author":"Fatahala","year":"2022","journal-title":"Med. Chem. (Los. Angeles)"},{"key":"B30","doi-asserted-by":"publisher","first-page":"177","DOI":"10.3390\/biomed3010015","article-title":"Early multi-target treatment of mild-to-moderate COVID-19, particularly in terms of non-steroidal anti-inflammatory drugs and indomethacin","volume":"3","author":"Fazio","year":"2023","journal-title":"BioMed"},{"key":"B31","doi-asserted-by":"publisher","first-page":"2548","DOI":"10.3390\/molecules23102548","article-title":"Synthesis, molecular docking and in vitro screening of some newly synthesized triazolopyridine, pyridotriazine and pyridine-pyrazole hybrid derivatives","volume":"23","author":"Flefel","year":"2018","journal-title":"Molecules"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fcimb.2021.654813","article-title":"Metabolic implications of oxidative stress and inflammatory process in SARS-CoV-2 pathogenesis: therapeutic potential of natural antioxidants","volume":"11","author":"Forcados","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/s43094-020-00115-0","article-title":"Anticancer activity of benzoxazole derivative (2015 onwards): a review","volume":"6","author":"Ghoshal","year":"2020","journal-title":"Futur. J. Pharm. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1007\/s10928-020-09690-4","article-title":"Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2","volume":"47","author":"Gomeni","year":"2020","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"B35","doi-asserted-by":"publisher","first-page":"6545","DOI":"10.4049\/jimmunol.165.11.6545","article-title":"Prostaglandin E2 selectively enhances the IgE-mediated production of IL-6 and granulocyte-macrophage colony-stimulating factor by mast cells through an EP1\/EP3-dependent mechanism","volume":"165","author":"Gomi","year":"2000","journal-title":"J. Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.rccar.2020.04.005","article-title":"COVID-19 and ACE -inhibitors and angiotensin receptor blockers-: the need to differentiate between early infection and acute lung injury","volume":"27","author":"Gonz\u00e1lez-rayas","year":"2020","journal-title":"Rev. Colomb. Cardiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2174\/0115734064386606250410111952","article-title":"Novel pyrrolopyrimidines as inhibitors of CLK4 and HER2: targeting promising anticancer pathways","volume":"21","author":"Gries","year":"2025","journal-title":"Med. Chem. (Los. Angeles)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"117655","DOI":"10.1016\/j.ejmech.2025.117655","article-title":"Design, synthesis, biophysical and biological evaluation of original condensed pyrrolopyrimidine and pyrrolopyridine ligands as anti-SARS-CoV-2 agents targeting G4","volume":"292","author":"Guillon","year":"2025","journal-title":"Eur. J. Med. Chem."},{"key":"B39","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1093\/ajh\/hpaa223","article-title":"SARS\u2013CoV-2 receptor ACE2 gene is associated with hypertension and severity of COVID 19: interaction with sex, obesity, and smoking","volume":"34","author":"Hamet","year":"2021","journal-title":"Am. J. Hypertens."},{"key":"B40","doi-asserted-by":"publisher","first-page":"12361","DOI":"10.1021\/acsomega.1c01604","article-title":"Design, synthesis, anticancer evaluation, enzymatic assays, and a molecular modeling study of novel pyrazole\u2013indole hybrids","volume":"6","author":"Hassan","year":"2021","journal-title":"ACS Omega"},{"key":"B41","doi-asserted-by":"publisher","first-page":"9281","DOI":"10.1039\/D3RA00297G","article-title":"Exploring novel derivatives of isatin-based schiff bases as multi-target agents: design, synthesis, in vitro biological evaluation, and in silico ADMET analysis with molecular modeling simulations","volume":"13","author":"Hassan","year":"2023","journal-title":"RSC Adv."},{"key":"B42","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.pharmthera.2004.06.003","article-title":"Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation","volume":"103","author":"Hata","year":"2004","journal-title":"Pharmacol. Ther."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2917","DOI":"10.1007\/s11033-021-06333-w","article-title":"COVID-19: imbalance of multiple systems during infection and importance of therapeutic choice and dosing of cardiac and anti-coagulant therapies","volume":"48","author":"Haybar","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2020.561674","article-title":"Celebrex adjuvant therapy on coronavirus disease 2019: an experimental study","volume":"11","author":"Hong","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3329\/jsr.v1i2.2299","article-title":"Synthesis and antimicrobial activities of some new thieno and furopyrimidine derivatives","volume":"1","author":"Hossain","year":"2009","journal-title":"J. Sci. Res."},{"key":"B47","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3892\/ijmm.2018.3937","article-title":"Anti-inflammatory and antioxidant effects of MOK, a polyherbal extract, on lipopolysaccharide-stimulated RAW 264.7 macrophages","volume":"43","author":"Hwang","year":"2019","journal-title":"Int. J. Mol. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphar.2023.1135145","article-title":"Therapeutic implications of current janus kinase inhibitors as anti-COVID agents: a review","volume":"14","author":"Jain","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"8158","DOI":"10.3390\/ijms22158158","article-title":"Efficient in vitro and in vivo anti\u2010inflammatory activity of a diamine\u2010pegylated oleanolic acid derivative","volume":"22","author":"Jannus","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2915","DOI":"10.1007\/s11030-022-10387-8","article-title":"Therapeutic potential of pyrrole and pyrrolidine analogs: an update","volume":"26","author":"Jeelan Basha","year":"2022","journal-title":"Mol. Divers."},{"key":"B51","volume-title":"Johns Hopkins Center for systems science and engineering COVID-19 map\u2014Johns Hopkins coronavirus resource Center","year":"2025"},{"key":"B52","doi-asserted-by":"publisher","first-page":"114738","DOI":"10.1016\/j.jep.2021.114738","article-title":"Anti-inflammatory effect of Kaba Sura Kudineer (AYUSH approved COVID-19 drug)-A siddha poly-herbal formulation against lipopolysaccharide induced inflammatory response in RAW-264.7 macrophages cells","volume":"283","author":"Jose","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"105180","DOI":"10.1016\/j.antiviral.2021.105180","article-title":"An update on the progress of galidesivir (BCX4430), a broad-spectrum antiviral","volume":"195","author":"Julander","year":"2021","journal-title":"Antivir. Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1039\/D5MD00196J","article-title":"Recent advances in targeting COX-2 for cancer therapy: a review","volume":"16","author":"Kassab","year":"2025","journal-title":"RSC Med. Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"30647","DOI":"10.1039\/d4ra04686b","article-title":"NSAIDs between past and present; a long journey towards an ideal COX-2 inhibitor lead","volume":"14","author":"Khalil","year":"2024","journal-title":"RSC Adv."},{"key":"B56","doi-asserted-by":"publisher","first-page":"3259","DOI":"10.3390\/jcm12093259","article-title":"Recent advances in understanding of the etiopathogenesis, diagnosis, and management of hair loss diseases","volume":"12","author":"Kinoshita-Ise","year":"2023","journal-title":"J. Clin. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1152\/ajprenal.00590.2010","article-title":"Toll-like receptor 4 activates NF-\u03baB and MAP kinase pathways to regulate expression of proinflammatory COX-2 in renal medullary collecting duct cells","volume":"302","author":"K\u00fcper","year":"2012","journal-title":"Am. J. Physiol. - Ren. Physiol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"12500","DOI":"10.1021\/acs.jmedchem.2c01005","article-title":"Targeting SARS-CoV-2 main protease for treatment of COVID-19: covalent inhibitors structure-activity relationship insights and evolution perspectives","volume":"65","author":"La Monica","year":"2022","journal-title":"J. Med. Chem."},{"key":"B59","doi-asserted-by":"publisher","first-page":"36","DOI":"10.2174\/1871523011312010006","article-title":"Drug interactions between non-steroidal anti-inflammatory drugs and cardiovascular treatments (except anti-agregant therapy)","volume":"12","author":"Lattuca","year":"2013","journal-title":"Antiinflamm. Antiallergy. Agents Med. Chem."},{"key":"B60","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nri3151","article-title":"Accessory molecules for toll-like receptors and their function","volume":"12","author":"Lee","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"B61","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/s41392-022-01249-8","article-title":"Small molecules in the treatment of COVID-19","volume":"7","author":"Lei","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"B62","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.farmac.2004.11.008","article-title":"3D-QSAR and preliminary evaluation of anti-inflammatory activity of series of N-pyrrolylcarboxylic acids","volume":"60","author":"Lessigiarska","year":"2005","journal-title":"Farmaco"},{"key":"B63","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/2162402X.2015.1074376","article-title":"TLR4 signaling promotes a COX-2\/PGE2\/STAT3 positive feedback loop in hepatocellular carcinoma (HCC) cells","volume":"5","author":"Lin","year":"2016","journal-title":"Oncoimmunology"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/j.cca.2011.02.028","article-title":"High-throughput screen of protein expression levels induced by cyclooxygenase-2 during influenza a virus infection","volume":"412","author":"Liu","year":"2011","journal-title":"Clin. Chim. Acta."},{"key":"B65","doi-asserted-by":"publisher","first-page":"13982","DOI":"10.1021\/acs.jafc.0c05064","article-title":"Quercetin and its metabolites inhibit recombinant human angiotensin-converting enzyme 2 (ACE2) activity","volume":"68","author":"Liu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"B66","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.redox.2017.03.001","article-title":"Xanthohumol ameliorates lipopolysaccharide (LPS)-induced acute lung injury via induction of AMPK\/GSK3\u03b2-Nrf2 signal axis","volume":"12","author":"Lv","year":"2017","journal-title":"Redox Biol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1111\/wej.12127","article-title":"The assessment of inflammatory activity and toxicity of treated sewage using RAW264.7 cells","volume":"29","author":"Makene","year":"2015","journal-title":"Water Environ. J."},{"key":"B68","doi-asserted-by":"publisher","first-page":"12","DOI":"10.4049\/jimmunol.2000413","article-title":"COVID-19 as an acute inflammatory disease","volume":"205","author":"Manjili","year":"2020","journal-title":"J. Immunol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0164632","article-title":"A novel class of small molecule agonists with preference for human over mouse TLR4 activation","volume":"11","author":"Marshall","year":"2016","journal-title":"PLoS One"},{"key":"B70","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/jbt.22656","article-title":"Discovery of novel pyrazole derivatives as a potent anti-inflammatory agent in RAW264.7 cells via inhibition of NF-\u0138B for possible benefit against SARS-CoV-2","volume":"35","author":"Masih","year":"2021","journal-title":"J. Biochem. Mol. Toxicol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"24","DOI":"10.18433\/JPPS32417","article-title":"Pyrrole as an important scaffold of anticancer drugs: recent advances","volume":"25","author":"Mateev","year":"2022","journal-title":"J. Pharm. Pharm. Sci."},{"key":"B72","doi-asserted-by":"publisher","first-page":"106826","DOI":"10.1016\/j.vph.2020.106826","article-title":"A new storm on the horizon in COVID-19: Bradykinin-induced vascular complications","volume":"137","author":"McCarthy","year":"2021","journal-title":"Vasc. Pharmacol."},{"key":"B73","doi-asserted-by":"publisher","first-page":"2068","DOI":"10.1002\/cmdc.202100150","article-title":"Design and synthesis of simplified polyketide analogs: new modalities beyond the rule of 5","volume":"16","author":"Menche","year":"2021","journal-title":"ChemMedChem"},{"key":"B74","first-page":"44","article-title":"Evaluation of the anti-inflammatory activity of novel synthesized pyrrole, pyrrolopyrimidine and spiropyrrolopyrimidine derivatives","volume":"3","author":"Mohame","year":"2012","journal-title":"Pharmacophore"},{"key":"B75","doi-asserted-by":"publisher","first-page":"145","DOI":"10.2478\/v10007-009-0016-9","article-title":"Synthesis of certain pyrrole derivatives as antimicro-bial agents","volume":"59","author":"Mohamed","year":"2009","journal-title":"Acta Pharm."},{"key":"B76","doi-asserted-by":"publisher","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-in fl ammatory and anti-microbial activities","volume":"45","author":"Mohamed","year":"","journal-title":"Eur. J. Med. Chem."},{"key":"B77","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.3390\/molecules15031882","article-title":"Synthesis of certain pyrimidine derivatives as antimicrobial agents and anti-inflammatory agents","volume":"15","author":"Mohamed","year":"","journal-title":"Molecules"},{"key":"B78","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1002\/ardp.201100056","article-title":"Synthesis of new pyrroles of potential anti-inflammatory activity","volume":"344","author":"Mohamed","year":"2011","journal-title":"Arch. Pharm. Weinh."},{"key":"B79","doi-asserted-by":"publisher","first-page":"2244","DOI":"10.1007\/s00044-012-0217-5","article-title":"Evaluation of the anti-inflammatory activity of some pyrrolo[2,3-d] pyrimidine derivatives","volume":"22","author":"Mohamed","year":"2013","journal-title":"Med. Chem. Res."},{"key":"B80","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1002\/ardp.201400387","article-title":"Novel antiviral compounds against gastroenteric viral infections","volume":"348","author":"Mohamed","year":"2015","journal-title":"Arch. Pharm. Weinh."},{"key":"B81","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.ejps.2018.10.022","article-title":"Evaluation of novel pyrrolopyrimidine derivatives as antiviral against gastroenteric viral infections","volume":"127","author":"Mohamed","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0313616","article-title":"Secondary metabolites of alternaria alternate appraisal of their SARS-CoV-2 inhibitory and anti-inflammatory potentials","volume":"20","author":"Moharram","year":"2025","journal-title":"PLoS One"},{"key":"B83","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1002\/chem.201403923","article-title":"Chemistry of lipid a: at the heart of innate immunity","volume":"21","author":"Molinaro","year":"2015","journal-title":"Chem. - A Eur. J."},{"key":"B84","doi-asserted-by":"publisher","first-page":"104315","DOI":"10.1016\/j.bioorg.2020.104315","article-title":"Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic","volume":"104","author":"Negi","year":"2020","journal-title":"Bioorg. Chem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-54082-5","article-title":"Roles of toll-like receptor 2\/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance","volume":"9","author":"Nie","year":"2019","journal-title":"Sci. Rep."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-88313-5","article-title":"Network pharmacology approach to decipher signaling pathways associated with target proteins of NSAIDs against COVID-19","volume":"11","author":"Oh","year":"2021","journal-title":"Sci. Rep."},{"key":"B87","doi-asserted-by":"publisher","first-page":"e1159","DOI":"10.1002\/cti2.1159","article-title":"Safety and potential efficacy of cyclooxygenase-2 inhibitors in coronavirus disease 2019","volume":"9","author":"Ong","year":"2020","journal-title":"Clin. Transl. Immunol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"108206","DOI":"10.1016\/j.jmgm.2022.108206","article-title":"Virtual and biochemical screening to identify the inhibitors of binding between SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2","volume":"114","author":"Park","year":"2022","journal-title":"J. Mol. Graph. Model."},{"key":"B89","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.ejmech.2018.08.023","article-title":"Pyrrolopyrimidines: an update on recent advancements in their medicinal attributes","volume":"157","author":"Pathania","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"B90","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1038\/s41581-020-00357-4","article-title":"Immunity, endothelial injury and complement-induced coagulopathy in COVID-19","volume":"17","author":"Perico","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"e0386524","DOI":"10.1128\/mbio.03865-24","article-title":"Identification of a series of pyrrolo-pyrimidine-based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication","volume":"16","author":"Pfannenstiel","year":"2025","journal-title":"MBio"},{"key":"B92","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1002\/ddr.21794","article-title":"Targeting cyclooxygenase enzyme for the adjuvant COVID-19 therapy","volume":"82","author":"Prasher","year":"2021","journal-title":"Drug Dev. Res."},{"key":"B93","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.2174\/0113852728306820240515054401","article-title":"Developments of Pyrrolo[2,3-d]pyrimidines with pharmaceutical potential","volume":"28","author":"Rashad","year":"2024","journal-title":"Curr. Org. Chem."},{"key":"B94","doi-asserted-by":"publisher","first-page":"6060","DOI":"10.1039\/d0ra10657g","article-title":"Research developments in the syntheses, anti-inflammatory activities and structure-activity relationships of pyrimidines","volume":"11","author":"Rashid","year":"2021","journal-title":"RSC Adv."},{"key":"B95","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fmicb.2020.00708","article-title":"Cyclooxygenase-2 inhibition reduces autophagy of macrophages enhancing extraintestinal pathogenic Escherichia coli infection","volume":"11","author":"Ren","year":"2020","journal-title":"Front. Microbiol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"524","DOI":"10.15585\/mmwr.mm7114a2","article-title":"Notes from the field: SARS-CoV-2 omicron variant infection in 10 persons within 90 days of previous SARS-CoV-2 Delta variant infection \u2014 four states, October 2021\u2013January 2022","volume":"71","author":"Roskosky","year":"2022","journal-title":"MMWR. Morb. Mortal. Wkly. Rep."},{"key":"B97","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1097\/00041552-200105000-00005","article-title":"Proinflammatory actions of angiotensins","volume":"10","author":"Ruiz-Ortega","year":"2001","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12950-021-00268-6","article-title":"Anti-inflammatory potential of quercetin in COVID-19 treatment","volume":"18","author":"Saeedi-Boroujeni","year":"2021","journal-title":"J. Inflamm. (United Kingdom)"},{"key":"B99","first-page":"553","volume-title":"Chapter 38 - zanubrutinib in liquid cancers a new horizon","author":"Sahu","year":"2026"},{"key":"B100","doi-asserted-by":"publisher","first-page":"107867","DOI":"10.1016\/j.bioorg.2024.107867","article-title":"Pyrrolo[2,3-d]pyrimidines as potential kinase inhibitors in cancer drug discovery: a critical review","volume":"153","author":"Sai Madhurya","year":"2024","journal-title":"Bioorg. Chem."},{"key":"B101","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fimmu.2021.606069","article-title":"The anti-inflammatory properties of phytochemicals and their effects on epigenetic mechanisms involved in TLR4\/NF-\u03baB-Mediated inflammation","volume":"12","author":"Saleh","year":"2021","journal-title":"Front. Immunol."},{"key":"B102","doi-asserted-by":"publisher","first-page":"89","DOI":"10.3389\/fphys.2017.00089","article-title":"Prostaglandin E(2) as a modulator of viral infections","volume":"8","author":"Sander","year":"2017","journal-title":"Front. Physiol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"1821","DOI":"10.1080\/14756366.2022.2090546","article-title":"Novel pyrrolopyrimidine derivatives: design, synthesis, molecular docking, molecular simulations and biological evaluations as antioxidant and anti-inflammatory agents","volume":"37","author":"Sayed","year":"2022","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"B104","doi-asserted-by":"publisher","first-page":"345","DOI":"10.3389\/fphar.2019.00345","article-title":"Importance of incorporating protein flexibility in molecule modeling: a theoretical study on type I1\/2 NIK inhibitors","volume":"10","author":"Shen","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"e202115695","DOI":"10.1002\/anie.202115695","article-title":"Inhibition of ACE2-Spike interaction by an ACE2 binder suppresses SARS-CoV-2 entry","volume":"61","author":"Shin","year":"2022","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"B106","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1007\/s43440-021-00303-6","article-title":"Understanding the role of ACE-2 receptor in pathogenesis of COVID-19 disease: a potential approach for therapeutic intervention","volume":"73","author":"Shirbhate","year":"2021","journal-title":"Pharmacol. Rep."},{"key":"B107","doi-asserted-by":"publisher","first-page":"752","DOI":"10.2174\/156802610791113423","article-title":"Orally bioavailable cathepsin K inhibitors with pyrrolopyrimidine scaffold","volume":"10","author":"Teno","year":"2010","journal-title":"Curr. Top. Med. Chem."},{"key":"B108","doi-asserted-by":"publisher","first-page":"107697","DOI":"10.1016\/j.jmgm.2020.107697","article-title":"Prioritizing potential ACE2 inhibitors in the COVID-19 pandemic: insights from a molecular mechanics-assisted structure-based virtual screening experiment","volume":"100","author":"Teral","year":"2020","journal-title":"J. Mol. Graph. Model."},{"key":"B109","doi-asserted-by":"publisher","first-page":"11011","DOI":"10.3390\/ijms252011011","article-title":"Pyrimidine derivatives as selective COX-2 inhibitors with anti-inflammatory and antioxidant properties","volume":"25","author":"Tyli\u0144ska","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B110","doi-asserted-by":"publisher","first-page":"627","DOI":"10.3390\/molecules25030627","article-title":"TLR4-targeting therapeutics: structural basis and computer-aided drug discovery approaches","volume":"25","author":"ul Ain","year":"2020","journal-title":"Molecules"},{"key":"B111","volume-title":"Omicron variant: what you need to know","year":"2025"},{"key":"B112","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ejphar.2007.08.034","article-title":"Preclinical pharmacology profile of CS-706, a novel cyclooxygenase-2 selective inhibitor, with potent antinociceptive and anti-inflammatory effects","volume":"578","author":"Ushiyama","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1056\/NEJMsr2005760","article-title":"Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19","volume":"382","author":"Vaduganathan","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B114","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/ctm2.371","article-title":"Interactions between ibuprofen, ACE2, renin\u2010angiotensin system, and spike protein in the lung. Implications for COVID\u201019","volume":"11","author":"Valenzuela","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"B115","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1248\/cpb.c16-00585","article-title":"Pyrrole oligoglycosides from the starfish Acanthaster planci suppress lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages","volume":"64","author":"Vien","year":"2016","journal-title":"Chem. Pharm. Bull."},{"key":"B116","doi-asserted-by":"publisher","first-page":"5588","DOI":"10.12659\/MSM.906857","article-title":"Toll-like receptor 4 (TLR4)\/cyclooxygenase-2 (COX-2) regulates prostate cancer cell proliferation, migration, and invasion by NF-\u03baB activation","volume":"24","author":"Wang","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"B117","doi-asserted-by":"publisher","first-page":"494","DOI":"10.2337\/db16-0773","article-title":"Macrophage cyclooxygenase-2 protects against development of diabetic nephropathy","volume":"66","author":"Wang","year":"2017","journal-title":"Diabetes"},{"key":"B118","doi-asserted-by":"publisher","first-page":"10941","DOI":"10.1021\/acs.joc.5c00918","article-title":"Synthesis and inhibitory assessment of ACE2 inhibitors for SARS-CoV-2: an in silico and in Vitro study","volume":"90","author":"Wang","year":"2025","journal-title":"J. Org. Chem."},{"key":"B119","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1159\/000499604","article-title":"Prostaglandin E2 regulates activation of mouse peritoneal macrophages by Staphylococcus aureus through toll-like receptor 2, toll-like receptor 4, and NLRP3 inflammasome signaling","volume":"12","author":"Wu","year":"2020","journal-title":"J. Innate Immun."},{"key":"B120","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.4049\/jimmunol.2001325","article-title":"Longitudinal peripheral blood transcriptional analysis reveals molecular signatures of disease progression in COVID-19 patients","volume":"206","author":"Yan","year":"2021","journal-title":"J. Immunol."},{"key":"B121","doi-asserted-by":"publisher","first-page":"4541","DOI":"10.1038\/s41467-020-18319-6","article-title":"Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor","volume":"11","author":"Yang","year":"2020","journal-title":"Nat. Commun."},{"key":"B122","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41392-021-00679-0","article-title":"The signal pathways and treatment of cytokine storm in COVID-19","volume":"6","author":"Yang","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"B123","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1515\/hc-2015-0204","article-title":"Novel synthesis and reactions of pyrazolyl-substituted tetrahydrothieno[2,3-c]isoquinoline derivatives","volume":"22","author":"Zaki","year":"2016","journal-title":"Heterocycl. Commun."},{"key":"B124","doi-asserted-by":"publisher","first-page":"4921","DOI":"10.1172\/JCI59777","article-title":"Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice","volume":"121","author":"Zhao","year":"2011","journal-title":"J. Clin. Invest."},{"key":"B125","doi-asserted-by":"publisher","first-page":"e0010402","DOI":"10.1371\/journal.pntd.0010402","article-title":"COX-2 is required to mediate crosstalk of ROS- dependent activation of MAPK\/NF- \u03ba B signaling with pro-inflammatory response and defense-related NO enhancement during challenge of macrophage-like cell line with Giardia duodenalis","volume":"16","author":"Zhao","year":"2022","journal-title":"PLoS Negl. Trop. Dis."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2025.1710650\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:19:52Z","timestamp":1767676792000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2025.1710650\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":125,"alternative-id":["10.3389\/fmolb.2025.1710650"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2025.1710650","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]},"article-number":"1710650"}}