{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:12:45Z","timestamp":1792033965450,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: The dual inhibition of the COX-2 and 5-LOX pathways, in addition to sEH inhibition, presents a superior approach to managing inflammation while mitigating the cardiovascular adverse effects typically associated with conventional NSAIDs. These multi-target agents are safer and more efficient as they inhibit the synthesis of pro-inflammatory leukotrienes while preserving cardioprotective epoxyeicosatrienoic acids. Methods: This study reports the development of multi-target inhibitors to mitigate inflammatory and cardiovascular conditions. We examined a series of tetrahydroindazole-sulfonamide hybrids (3a\u2013g and 4a\u2013e) against the enzymes COX-1\/2, 5-LOX, and sEH. Results: Compound 3b outperformed celecoxib as a multi-target agent, inhibiting COX-2 (IC50 = 0.08 \u00b5M, SI = 82), 5-LOX (IC50 = 0.46 \u00b5M), and sEH (IC50 = 21.95 nM) in many metrics. In cellular experiments, 3b showed strong cardioprotective and anti-inflammatory effects, significantly reducing TNF-\u03b1 (65.58%), LDH (76.26%), and CK-MB (76.76%) levels compared to LPS-treated controls. Molecular docking validated these findings, indicating that 3b was comparable to celecoxib at the COX-2 site via a thorough six hydrogen-bond network and achieves considerable sEH affinity through specialized halogen bonding and aromatic stacking. These results indicate that 3b effectively provides dual anti-inflammatory and cardioprotective effects. Conclusions: Our findings suggest that targeting the COX\/5-LOX\/sEH pathways simultaneously offers a balanced multi-target profile for treating complex inflammatory diseases while minimizing cardiovascular risks.<\/jats:p>","DOI":"10.3390\/ph19060843","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"843","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design, Synthesis, and Biological Evaluation of Tetrahydroindazole-Based Sulfonamides as Potential Multi-Target Anti-Inflammatory Agents"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3460-0667","authenticated-orcid":false,"given":"Mohammed A. I.","family":"Elbastawesy","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Abdelhafez","sequence":"additional","affiliation":[{"name":"PharmaHelp Foundation Inc., Falls Church, VA 22046, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5231-8932","authenticated-orcid":false,"given":"Abdullah","family":"Yahya Abdullah Alzahrani","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, King Khalid University, Abha 61413, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-917X","authenticated-orcid":false,"given":"Bandar A.","family":"Alyami","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran 11001, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6633-2798","authenticated-orcid":false,"given":"Hanyu","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud S.","family":"Abdelbaset","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Gaber","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahaa G. M.","family":"Youssif","sequence":"additional","affiliation":[{"name":"Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-3191","authenticated-orcid":false,"given":"Stefan","family":"Brase","sequence":"additional","affiliation":[{"name":"Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6629-6102","authenticated-orcid":false,"given":"Hiroyuki","family":"Konno","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biological Engineering, Graduate School of Science and Engineering, Yamagata University, Yonezawa, Yamagata 992-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Guan, A., Bei, X., Jin, C., Xie, J., Guo, J., and Li, X. (2026). Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Meloxicam. Molecules, 31.","DOI":"10.22541\/au.176914637.76290558\/v1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.bioorg.2017.09.009","article-title":"Novel diphenylthiazole derivatives with multi-target mechanism: Synthesis, docking study, anticancer and anti-inflammatory activities","volume":"75","author":"Abdelazeem","year":"2017","journal-title":"Bioorg. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Adhikary, K., Karn, A., Ganguly, K., and Banerjee, P. (2026). Anti-Inflammatory Benefits of Shatavari Saponins by Inhibiting COX-2 without Digestive Side Effects. Health Benefits of Asparagus racemosus (Shatavari), CRC Press.","DOI":"10.1201\/9781003563983-23"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/cpt.70054","article-title":"Nonsteroidal Anti-Inflammatory Drugs and Risk of Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis","volume":"119","author":"Tawfik","year":"2026","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1007\/s10787-026-02129-1","article-title":"Evaluating adverse events reported for non-steroidal anti-inflammatory drugs in osteoarthritis: A real-world pharmacovigilance study","volume":"34","author":"Zhang","year":"2026","journal-title":"Inflammopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2200024","DOI":"10.1002\/ardp.202200024","article-title":"New pyrimidine\/thiazole hybrids endowed with analgesic, anti-inflammatory, and lower cardiotoxic activities: Design, synthesis, and COX-2\/sEH dual inhibition","volume":"355","author":"Taher","year":"2022","journal-title":"Arch. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"33494","DOI":"10.1021\/acsomega.4c00870","article-title":"New diaryl-1, 2, 4-triazolo [3, 4-a] pyrimidine hybrids as selective COX-2\/sEH dual inhibitors with potent analgesic\/anti-inflammatory and cardioprotective properties","volume":"9","author":"Youssif","year":"2024","journal-title":"ACS Omega"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104890","DOI":"10.1016\/j.bioorg.2021.104890","article-title":"Design, synthesis, and biological evaluation of new pyrimidine-5-carbonitrile derivatives bearing 1, 3-thiazole moiety as novel anti-inflammatory EGFR inhibitors with cardiac safety profile","volume":"111","author":"Taher","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105302","DOI":"10.1016\/j.bioorg.2021.105302","article-title":"Novel 1, 5-diaryl pyrazole-3-carboxamides as selective COX-2\/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects","volume":"116","author":"Hendawy","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115712","DOI":"10.1016\/j.ejmech.2023.115712","article-title":"Discovery and optimization of 2, 3-diaryl-1, 3-thiazolidin-4-one-based derivatives as potent and selective cytotoxic agents with anti-inflammatory activity","volume":"259","author":"Shawky","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Leal-Ramos, O.J., Arias-Ruiz, L.F., Huerta-Vel\u00e1zquez, J.M., Lamoreaux-Aguayo, J.P., Butcher, D., L\u00f3pez-Cuellar, A.B., Orozco-Jim\u00e9nez, K.I., and Torres-Bugar\u00edn, O. (2025). Mechanisms Involved in the Adverse Cardiovascular Effects of Selective Cyclooxygenase-2 Inhibitors. Cardiovasc. Med., 28.","DOI":"10.3390\/cardiovascmed28010005"},{"key":"ref_12","unstructured":"Jamieson, K.L. (2020). Cardioprotective Effects of Soluble Epoxide Hydrolase Inhibition Following Myocardial Infarction. [Ph.D. Thesis, University of Alberta]."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Das Mahapatra, A., Choubey, R., and Datta, B. (2020). Small molecule soluble epoxide hydrolase inhibitors in multitarget and combination therapies for inflammation and cancer. Molecules, 25.","DOI":"10.3390\/molecules25235488"},{"key":"ref_14","unstructured":"Meloun, A. (2025). Cysteine Protease Activity in Allergen Recognition and Initiation of TH2 Allergic Responses. [Ph.D. Thesis, The University of Alabama at Birmingham]."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e70114","DOI":"10.1111\/cbdd.70114","article-title":"A Comprehensive Review on the Advancements of Dual COX-2\/5-LOX Inhibitors as Anti-Inflammatory Drugs","volume":"105","author":"Agrawal","year":"2025","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_16","first-page":"901","article-title":"Licofelone as a dual COX\/5-LOX inhibitor: A comprehensive review of its Physicochemical, Pharmacological, and therapeutic profiles in osteoarthritis and neurodegenerative disorders","volume":"48","author":"Abuelella","year":"2025","journal-title":"Bull. Pharm. Sci. Assiut Univ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1080\/07391102.2024.2425404","article-title":"In silico strategies to recognize pharmacological constraints contrary to COX-2 and 5-LOX","volume":"44","author":"Neha","year":"2026","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chistyakov, D.V., Chistyakov, V.V., and Sergeeva, M.G. (2025). Oxylipins in Atherosclerosis: Their Role in Inflammation, Diagnosis, and Therapeutic Perspectives. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262110577"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.2174\/0929867311320130013","article-title":"Rationally designed multitarget agents against inflammation and pain","volume":"20","author":"Hwang","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e14569","DOI":"10.1016\/j.heliyon.2023.e14569","article-title":"Natural product-driven dual COX-LOX inhibitors: Overview of recent studies on the development of novel anti-inflammatory agents","volume":"9","author":"Mukhopadhyay","year":"2023","journal-title":"Heliyon"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"115180","DOI":"10.1016\/j.ejmech.2023.115180","article-title":"4-(5-Amino-pyrazol-1-yl) benzenesulfonamide derivatives as novel multi-target anti-inflammatory agents endowed with inhibitory activity against COX-2, 5-LOX and carbonic anhydrase: Design, synthesis, and biological assessments","volume":"250","author":"Ragab","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1002\/ardp.201200193","article-title":"Trimethyl-4-oxo-4, 5, 6, 7-tetrahydroindazole-1-acetic acid: A new Lead compound with selective COX-2 inhibitory activity","volume":"345","author":"Ozadali","year":"2012","journal-title":"Arch. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5196","DOI":"10.1039\/D5MD00336A","article-title":"Indazole\u2014An emerging privileged scaffold: Synthesis and its biological significance","volume":"16","author":"Singampalli","year":"2025","journal-title":"RSC Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0223-5234(02)01444-7","article-title":"Cytotoxic analogues of 2, 6-bis (arylidene) cyclohexanones","volume":"38","author":"Dimmock","year":"2003","journal-title":"Eur. J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.ejmech.2013.11.011","article-title":"Synthesis and evaluation of the antiparasitic activity of bis-(arylmethylidene) cycloalkanones","volume":"71","author":"Braga","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/j.ejmech.2016.11.006","article-title":"Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs\/LOX inhibitors endowed with anti-inflammatory activity","volume":"127","author":"Abdelrahman","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.36838\/v8i5.29","article-title":"Reviewing: Monoclonal Antibody Therapies Targeting IL-6 & TNF-Alpha against Rheumatoid Arthritis","volume":"8","author":"Singh","year":"2026","journal-title":"Int. J. High Sch. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e410926","DOI":"10.1590\/acb410926","article-title":"Cardioprotective effects of the ranolazine in myocardial infarction mediated by stimulation of the endogenous mediators involved in ischemic preconditioning","volume":"41","author":"Tantray","year":"2026","journal-title":"Acta Cir. Bras."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s12964-025-02132-z","article-title":"L- and D-Lactate: Unveiling their hidden functions in disease and health","volume":"23","author":"Li","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_30","first-page":"287","article-title":"Comparative Evaluation of Serum CK-Total, CK-MB, and Lactate Dehydrogenase Levels in Type 2 Diabetes Mellitus and Their Association with Cardiovascular Risk","volume":"16","author":"Kava","year":"2026","journal-title":"Eur. J. Cardiovasc. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e2308910","DOI":"10.1002\/advs.202308910","article-title":"Inflammation-Targeted Nanomedicines Alleviate Oxidative Stress and Reprogram Macrophages Polarization for Myocardial Infarction Treatment","volume":"11","author":"Hu","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1177\/0023677215570087","article-title":"Lipopolysaccharide-induced inflammatory liver injury in mice","volume":"49","author":"Hamesch","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.ejps.2011.09.020","article-title":"Antiinflammatory effects of matrine in LPS-induced acute lung injury in mice","volume":"44","author":"Zhang","year":"2011","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.62383\/ikg.v3i1.2799","article-title":"Preparation and Molecular Docking of Some Heterocyclic Compounds Containing Nitrogen and Oxygen Atoms","volume":"3","author":"Jassim","year":"2026","journal-title":"Inov. Kesehat. Glob."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1007\/s10787-026-02134-4","article-title":"Computationally guided synthesis and biological profiling of chalcones as antioxidant and anti-inflammatory activities","volume":"34","author":"Kharl","year":"2026","journal-title":"Inflammopharmacology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E6774","DOI":"10.1073\/pnas.1703925114","article-title":"Conformational and chemical selection by a trans-acting editing domain","volume":"114","author":"Danhart","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1021\/acs.chemrev.0c01263","article-title":"Chemical aspects of human and environmental overload with fluorine","volume":"121","author":"Han","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3109\/03602539408998319","article-title":"Effects of fluorine substitution on drug metabolism: Pharmacological and toxicological implications","volume":"26","author":"Park","year":"1994","journal-title":"Drug Metab. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Oniga, S.D., Pacureanu, L., Stoica, C.I., Palage, M.D., Cr\u0103ciun, A., Rusu, L.R., Crisan, E.-L., and Araniciu, C. (2017). COX inhibition profile and molecular docking studies of some 2-(trimethoxyphenyl)-thiazoles. Molecules, 22.","DOI":"10.3390\/molecules22091507"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1021\/jm201468j","article-title":"Discovery of inhibitors of soluble epoxide hydrolase: A target with multiple potential therapeutic indications","volume":"55","author":"Shen","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13041-023-01008-y","article-title":"Transient inhibition of microsomal prostaglandin E synthase-1 after status epilepticus blunts brain inflammation and is neuroprotective","volume":"16","author":"Yasmen","year":"2023","journal-title":"Mol. Brain"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1007\/s00044-025-03393-6","article-title":"Synthesis, hydrolysis, and COX-2\/15-LOX inhibitory evaluation of 4-Acetamidophenyl 4-Bromobenzoates","volume":"34","author":"Afzal","year":"2025","journal-title":"Med. Chem. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1097\/CM9.0000000000003792","article-title":"Diabetic vascular calcification inhibited by soluble epoxide hydrolase gene deletion via regressing NID2-mediated IGF2-ERK1\/2 signaling pathway","volume":"138","author":"Cai","year":"2025","journal-title":"Chin. Med. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1128\/CDLI.12.1.60-67.2005","article-title":"Acute inflammatory response to endotoxin in mice and humans","volume":"12","author":"Copeland","year":"2005","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/nri2402","article-title":"Harmful molecular mechanisms in sepsis","volume":"8","author":"Rittirsch","year":"2008","journal-title":"Nat. Rev. Immunol."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/6\/843\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:09:25Z","timestamp":1780535365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/6\/843"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":45,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ph19060843"],"URL":"https:\/\/doi.org\/10.3390\/ph19060843","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]}}}