Synthetic strategies and biological screening of novel pyrazolines as COX inhibitors

Year 2025, Volume: 4 Issue: 2, 64 - 76, 31.08.2025

Betül Kaya , Begüm Nurpelin Sağlık , Yusuf Özkay , Zafer Asım Kaplancıklı

https://doi.org/10.55971/EJLS.1712793

Abstract

In this study, a novel series of pyrazolines was afforded by the reaction of 2-hydrazinyl-N-(4-aminosulfonylphenyl)acetamide (2) and chalcone intermediates. The structures of target compounds were confirmed by IR, 1H NMR, 13C NMR and HRMS. The synthesized compounds were further evaluated for their in vitro COX inhibitory activity in order to discover new, effective and safer anti-inflammatory agents. Most of the compounds were more selective for COX-2 isozyme than COX-1. All compounds were weak inhibitors when compared to standard drugs ibuprofen, celecoxib and nimesulide. Among them, compounds 4a, 4e and 4f were the most potent inhibitors of COX-2. These findings suggest that these compounds could be lead compounds for further development as selective COX-2 inhibitors.

Keywords

Anti-inflammatory , COX-1 , COX-2 , pyrazoline

Ethical Statement

Ethics committee approval is not required as there are no in vivo or clinical studies.

Supporting Institution

This study was financially supported by Anadolu University Scientific Projects Fund, Project No: 1803S052

Project Number

1803S052

Thanks

As the authors of this study, we thank Anadolu University Faculty of Pharmacy Central Research Laboratory (MERLAB), for their support and contributions.

References

• Reddy KK, Vidya Rajan VK, Gupta A, Aparoy P, Reddanna P. Exploration of binding site pattern in arachidonic acid metabolizing enzymes, cyclooxygenases and lipoxygenases. BMC Res Notes. (2015);8:152. https://doi.org/10.1186/s13104-015-1101-4
• Abdelgawad MA, Labib MB, Ali WAM, Kamel G, Azouz AA, EL-Nahass E. Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: histopathological and docking studies. Bioorg Chem. (2018);78:103–114. https://doi.org/10.1016/j.bioorg.2018.03.011
• Elgohary MK, Abo-Ashour MF, Abd El Hadi SR, El Hassab MA, Abo-El Fetoh M E, Afify H, Abdel-Aziz HA, Abou-Seri SM. Novel anti-inflammatory agents featuring phenoxy acetic acid moiety as a pharmacophore for selective COX-2 inhibitors: Synthesis, biological evaluation, histopathological examination and molecular modeling investigation. Bioorg Chem. (2024);152:107727. https://doi.org/10.1016/j.bioorg.2024.107727
• Ragab FAEF, Mohammed EI, Jaleel GAA, Abd El-Rahman AAM, Nissan YM. Synthesis of hydroxybenzofuranyl-pyrazolyl and hydroxyphenyl-pyrazolyl chalcones and their corresponding pyrazoline derivatives as COX inhibitors, anti-inflammatory and gastroprotective agents. Chem Pharm Bull. (2020);68(8):742-752. https://doi.org/10.1248/cpb.c20-00193
• Abdellatif KR, Abdelall EK, Elshemy HA, Lamie PF, Elnahaas E, Amin DM. Design, synthesis of new anti-inflammatory agents with a pyrazole core: COX-1/COX-2 inhibition assays, anti-inflammatory, ulcerogenic, histopathological, molecular modeling, and ADME studies. J Mol Struct. (2021);1240:130554. https://doi.org/10.1016/j.molstruc.2021.130554
• Perrone MG, Lofrumento DD, Vitale P, De Nuccio F, La Pesa V, Panella A, Calvello R, Cianciulli A, Panaro MA, Scilimati A. Selective cyclooxygenase-1 inhibition by P6 and gastrotoxicity: preliminary investigation. Pharmacology. (2015);95:22–28. https://doi.org/10.1159/000369826
• Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol. (2013);19(12):1861–1876. https://doi.org/10.3748/wjg.v19.i12.1861
• Tanaka A, Hase S, Miyazawa T, Ohno R, Takeuchi K. Role of cyclooxygenase (COX)-1 and COX-2 inhibition in nonsteroidal anti-inflammatory drug-induced intestinal damage in rats: relation to various pathogenic events. J Pharmacol Exp Ther. (2002);303(3):1248–1254. https://doi.org/10.1124/jpet.102.041715
• Garcia-Rodriguez LA, Hern´ andez-Diaz S. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs, Am J Med. (2001);110:20-27. https://doi.org/10.1016/s0002-9343(00)00682-3
• Ruan CH, So SP, Ruan KH. Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: mechanisms of COX-2 inhibitor risk to heart disease, Life Sci. (2011);88:24–30. https://doi.org/10.1016/J.LFS.2010.10.017
• Hwang SH, Wecksler AT, Wagner K, Hammock BD. Rationally designed multitarget agents against inflammation and pain. Curr Med Chem. (2013);20(13):1783–1799. https://doi.org/10.2174/0929867311320130013
• Sun SX, Lee KY, Bertram CT, Goldstein JL. Withdrawal of COX-2 selective inhibitors rofecoxib and valdecoxib: impact on NSAID and gastroprotective drug prescribing and utilization. Curr Med Res Opin. (2007);23(8):1859-1866. https://doi.org/10.1185/030079907X210561
• Ghifari TA, Wulan FF, Astuti E, Suryanti V, Putri DEK, Nur H, Wahyuningsih TD. Synthesis of furan-based pyrazoline as an anticancer agent: an in vitro and in silico approach toward COX-2 inhibition. J Mol Struct. (2025);1337:142125. https://doi.org/10.1016/j.molstruc.2025.142125
• Ayman R, Abusaif MS, Radwan AM, Elmetwally AM, Ragab A. Development of novel pyrazole, imidazo [1, 2-b] pyrazole, and pyrazolo [1, 5-a] pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential. Eur J Med Chem. (2023);249:115138. https://doi.org/10.1016/j.ejmech.2023.115138
• Labib MB, Fayez AM, EL-Shaymaa EN, Awadallah M, Halim PA. Novel tetrazole-based selective COX-2 inhibitors: Design, synthesis, anti-inflammatory activity, evaluation of PGE2, TNF-α, IL-6 and histopathological study. Bioorg Chem. (2020);104:104308. https://doi.org/10.1016/j.bioorg.2020.104308
• Al-Turki DA, Al-Omar MA, Abou-Zeid LA, Shehata IA, Al-Awady MS. Design, synthesis, molecular modeling and biological evaluation of novel diaryl heterocyclic analogs as potential selective cyclooxygenase-2 (COX-2) inhibitors. Saudi Pharm J. (2017);25(1):59-69. https://doi.org/10.1016/j.jsps.2015.07.001
• Harras MF, Sabour R, Alkamali OM. Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents. Med Chem Commun. (2019);10:1775–1788. https://doi.org/10.1039/C9MD00228F
• Nehra B, Rulhania S, Jaswal S, Kumar B, Singh G, Monga V. Recent advancements in the development of bioactive pyrazoline derivatives. Eur J Med Chem. (2020);205:112666. https://doi.org/10.1016/j.ejmech.2020.112666
• Abdel-Sayed MA, Bayomi SM, El-Sherbeny MA, Abdel-Aziz NI, ElTahir KEH, Shehatou GSG, Abdel-Aziz AA-M. Synthesis, antiinflammatory, analgesic, COX-1/2 inhibition activities and molecular docking study of pyrazoline derivatives. Bioorg Med Chem. (2016);24:2032-2042 https://doi.org/10.1016/j.bmc.2016.03.032
• Elgohary MK, Abd El Hadi SR, Abo-Ashour MF, Abo-El Fetoh ME, Afify H, Abdel-Aziz HA, Abou-Seri SM. Fragment merging approach for the design of thiazole/thiazolidine clubbed pyrazoline derivatives as anti-inflammatory agents: Synthesis, biopharmacological evaluation and molecular modeling studies. Bioorg Chem. (2023);139:106724. https://doi.org/10.1016/j.bioorg.2023.106724
• Mantzanidou M, Pontiki E, Hadjipavlou-Litina D. Pyrazoles and pyrazolines as anti-inflammatory agents. Molecules. (2021);26(11):3439-3457. https://doi.org/10.3390/molecules26113439
• Altintop MD, Temel HE, Özdemir A. Microwave-assisted synthesis of a series of 4, 5-dihydro-1H-pyrazoles endowed with selective COX-1 inhibitory potency. J Serb Chem Soc. (2023);88(4):355-365. https://doi.org/10.2298/JSC220907001A
• Raut DG, Lawand AS, Kadu VD, Hublikar MG, Patil SB, Bhosale DG, Bhosale RB. Synthesis of asymmetric thiazolyl pyrazolines as a potential antioxidant and anti-inflammatory agents. Polycycl Aromat Compd. (2020);42(1):70–79. https://doi.org/10.1080/10406638.2020.1716028
• Kharbanda C, Alam MS, Hamid H, Javed K, Bano S, Dhulap S, Ali Y, Nazreen S, Haider S. Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents. Bioorg Med Chem. (2014);22:5804–5812. https://doi.org/10.1016/j.bmc.2014.09.028
• Yan R, Huang X, Deng X, Song M. Synthesis and activity evaluation of some pyrazole–pyrazoline derivatives as dual anti-inflammatory and antimicrobial Agents. Polycycl Aromat Compd. (2021);42(8):5006–5019. https://doi.org/10.1080/10406638.2021.1919156
• Sihag M, Manuja A, Rani S, Soni R, Rani N, Malik S, Bhardwaj K, Kumar B, Kinger M, Miglani M, Aneja DK. Synthesis of pyrazole and pyrazoline derivatives of β-ionone: Exploring anti-inflammatory potential, cytotoxicity, and molecular docking insights. Eur J Med Chem Rep. (2024);12:100204. https://doi.org/10.1016/j.ejmcr.2024.100204
• Thach TD, Nguyen TMT, Nguyen TAT, Dang CH, Luong TB, Dang VS, Banh KS, Luc VS, Nguyen TD. Synthesis and antimicrobial, antiproliferative and anti-inflammatory activities of novel 1, 3, 5-substituted pyrazoline sulphonamides. Arab J Chem. (2021);14(11):103408. https://doi.org/10.1016/j.arabjc.2021.103408
• Kaya Çavuşoğlu B, Sağlık BN, Acar Cevik U, Osmaniye D, Levent S, Özkay Y, Kaplancıklı ZA. Design, synthesis, biological evaluation, and docking studies of some novel chalcones as selective COX‐2 inhibitors. Arch Pharm. (2021);354(3):2000273. https://doi.org/10.1002/ardp.202000273
• Biovision COX‐1 Fluorescent Inhibitor Screening Kit (Catalog No: K548‐100) manual, http://www.biovision.com/manuals/K548.pdf
• Biovision COX‐2 Fluorescent Inhibitor Screening Kit (Catalog No:K547‐100) manual, http://www.biovision.com/manuals/K547.pdf
• Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. (2017);7:42717. https://doi.org/10.1038/srep42717