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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry


ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Pro- and Anti-Inflammatory Cytokine Expression Levels in Macrophages; An Approach to Develop Indazolpyridin-methanones as Novel Inflammation Medication

Author(s): Manikandan Alagumuthu, Vanshika Srivastava, Manisha Shah, Sivakumar Arumugam, Mohandoss Sonaimuthu and Napoleon Ayyakannu Arumugam *

Volume 19 , Issue 4 , 2020

Page: [425 - 435] Pages: 11

DOI: 10.2174/1871523019666191226104724


Background: Macrophages play a serious part in the instigation, upkeep, and resolution of inflammation. They are activated or deactivated during inflammation progression. Activation signals include cytokines (IF-γ, granulocyte-monocyte colonystimulating factor (GM-CSF), and TNF-α), extracellular matrix proteins, and other chemical mediators. Activated macrophages are deactivated by anti-inflammatory cytokines (IL- 10 and TGF-β (transforming growth factor-beta) and cytokine antagonists that are mainly produced by macrophages. Based on this, the present study aimed to develop novel (E)- Benzylidene-indazolpyridin methanones (Cpd-1-10) as effective anti-inflammatory agents by analyzing pro- and anti-inflammatory cytokine levels in macrophages.

Objectives: To determine the anti-inflammatory effect of indazolpyridin-methanones by examining pro- and anti-inflammatory interleukin levels in J77A.1 macrophages.

Methods: Expression of cytokines such as TNF-α, IL-1β, IL-6 and IL-10 serum levels measured by ELISA method. Anti-cancer and cytotoxicity studies were carried out by MTT assay. COX-2 seems to be associated with cancers and atypical developments in the duodenal tract. So, a competitive ELISA based COX-2 inhibition assay was done. To validate the inhibitory potentials and to get more insight into the interaction of COX-2 with Cpd1-10, molecular docking was performed.

Results: Briefly, the COX-2 inhibitory relative activity was found to be in between the range of 80-92% (Diclofenac showed 84%, IC50 0.95 μM).

Conclusion: Cytotoxicity effect of the compounds against breast cancer cell lines found excellent and an extended anticancer study ensured that these compounds are also alternative therapeutic agents against breast cancer. Among all the tested cancer cell lines, the anti- cancer effect on breast cancer was exceptional for the most active compounds Cpd5 and Cpd9.

Keywords: Anti-inflammation, benzylidene-indazolpyridin methanones, COX-2, cytotoxicity, HRBC membrane stabilization, cytokine.

Graphical Abstract
Williams, C.S.; Mann, M.; DuBois, R.N. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene, 1999, 18(55), 7908-7916.
[] [PMID: 10630643]
Ricciotti, E.; FitzGerald, G.A. Prostaglandins and inflammation. Arterioscler. Thromb. Vasc. Biol., 2011, 31(5), 986-1000.
[] [PMID: 21508345]
Seibert, K.; Masferrer, J.L. Role of inducible cyclooxygenase (COX-2) in inflammation. Receptor, 1994, 4(1), 17-23.
[PMID: 8038702]
Hawkey, C.J. COX-1 and COX-2 inhibitors. Best Pract. Res. Clin. Gastroenterol., 2001, 15(5), 801-820.
[] [PMID: 11566042]
Bertolini, A.; Ottani, A.; Sandrini, M. Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks. Curr. Med. Chem., 2002, 9(10), 1033-1043.
[] [PMID: 12733982]
Pannunzio, A.; Coluccia, M. Cyclooxygenase-1 (COX-1) and COX-1 inhibitors in cancer: a review of oncology and medicinal chemistry literature. Pharmaceuticals (Basel), 2018, 11(4), 101.
[] [PMID: 30314310]
Zarghi, A.; Arfaei, S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran. J. Pharm. Res., 2011, 10(4), 655-683.
[PMID: 24250402]
Chelli, S.M.; Manikandan, A.; Sridhar, P.; Sivakumar, A.; Siva Kumar, B.; Sabbasani, R.R. Drug repurposing of novel quinoline acetohydrazide derivatives as potent COX-2 inhibitors and anti-cancer agents. J. Mol. Struct., 2018, 1154, 437-444.
Manikandan, A.; Ravichandran, S.; Sathiyanarayanan, K.I.; Sivakumar, A. Efficacy and rationale of 2-(4-phenylquinolin-2-yl) phenols as COX-2 inhibitors; an approach to emergent the small molecules as the anti-inflammatory and analgesic therapeutics. Inflammopharmacology, 2017, 25, 621-631.
[] [PMID: 28378280]
Nørregaard, R.; Kwon, T.H.; Frøkiær, J. Physiology and pathophysiology of cyclooxygenase-2 and prostaglandin E2 in the kidney. Kidney Res. Clin. Pract., 2015, 34(4), 194-200.
[] [PMID: 26779421]
Morteau, O. Prostaglandins and inflammation: the cyclooxygenase controversy. Arch. Immunol. Ther. Exp. (Warsz.), 2000, 48(6), 473-480.
[PMID: 11197601]
Hanna, V.S.; Hafez, E.A.A. Synopsis of arachidonic acid metabolism: A review. J. Adv. Res., 2018, 11, 23-32.
[] [PMID: 30034873]
Thomas, G.J.; Morton, C.A. Cyclooxygenase in cancer prevention and treatments for Actinic Keratosis. Dermatol. Ther. (Heidelb.), 2017, 7(Suppl. 1), 21-29.
[] [PMID: 28150108]
Mazhar, D.; Ang, R.; Waxman, J. COX inhibitors and breast cancer. Br. J. Cancer, 2006, 94(3), 346-350.
[] [PMID: 16421592]
Chow, L.W.; Loo, W.T.; Toi, M. Current directions for COX-2 inhibition in breast cancer. Biomed. Pharmacother., 2005, 59(Suppl. 2), S281-S284.
[] [PMID: 16507393]
Farooqui, M.; Li, Y.; Rogers, T.; Poonawala, T.; Griffin, R.J.; Song, C.W.; Gupta, K. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br. J. Cancer, 2007, 97(11), 1523-1531.
[] [PMID: 17971769]
Liu, B.; Qu, L.; Yan, S. Cyclooxygenase-2 promotes tumor growth and suppresses tumor immunity. Cancer Cell Int., 2015, 15, 106.
[] [PMID: 26549987]
Griswold, D.E.; Adams, J.L. Constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2): rationale for selective inhibition and progress to date. Med. Res. Rev., 1996, 16(2), 181-206.
[<181:AID-MED3>3.0.CO;2-X] [PMID: 8656779]
Napoleon, A.A.; Nawaz Khan, F.R.; Jeong, E.D.; Chung, E.H. Potential anti-tubercular agents: Hexahydro-3-phenyl-indazol-2-yl(pyridin-4-yl) methanones from anti-tubercular drug isoniazid and bis (substituted-benzylidene) cycloalkanones. Chin. Chem. Lett., 2015, 26, 567-571.
Alagumuthu, M.; Arumugam, S. Molecular docking, discovery, synthesis, and pharmacological properties of new 6-substituted-2-(3-phenoxyphenyl)-4-phenyl quinoline derivatives; an approach to developing potent DNA gyrase inhibitors/antibacterial agents. Bioorg. Med. Chem., 2017, 25(4), 1448-1455.
[] [PMID: 28094220]
Manikandan, A.; Moharil, P.; Sathishkumar, M.; Muñoz-Garay, C.; Sivakumar, A. Therapeutic investigations of novel indoxyl-based indolines: a drug target validation and structure-activity relationship of angiotensin-converting enzyme inhibitors with cardiovascular regulation and thrombolytic potential. Eur. J. Med. Chem., 2017, 141, 417-426.
[] [PMID: 29032034]
Petrovic, N.; Murray, M.; Using, N.; Using, N. N,N′,N′-tetramethyl-p-phenylenediamine (TMPD) to assay cyclooxygenase activity in vitro. Methods Mol. Biol., 2010, 594, 129-140.
[] [PMID: 20072914]
Alagumuthu, M.; Arumugam, S. Molecular explorations of substituted 2-(4-phenylquinolin-2-yl) phenols as phosphoinositide 3-kinase inhibitors and anticancer agents. Cancer Chemother. Pharmacol., 2017, 79(2), 389-397.
[] [PMID: 28054203]
Manikandan, A.; Ravichandran, S.; Kumaravel, K.; Sivakumar, A.; Rethna, P. Molecular docking and in vitro evaluations of Hippocampus trimaculatus (seahorse) extracts as anti-inflammatory compounds. Int. J. Bioinform. Res. Appl., 2016, 12(4), 355-371.
Manikandan, A.; Nemani, SC.; Sadheeshkumar, V.; Sivakumar, A. Spectroscopic investigations for photostability of Diclofenac sodium complexed with hydroxy propyl-β-cyclodextrin. J. Appl. Pharm. Sci., 2016, 6, 98-103.
Rajesh, K.M.; Manikandan, A.; Violet, D.V. Synthesis, characterization and molecular evaluation of substituted indoline based dihydroxy-thiocarbamides as selective COX-2 inhibitors. J. Heterocycl. Chem., 2018, 55, 1658-1668.
Alves, C.C.; Da Costa, C.F.; De Castro, S.B.; Correa, T.A.; Santiago, G.O.; Diniz, R.; Ferreira, A.P.; De Almeida, M.V. Synthesis and evaluation of cytotoxicity and inhibitory effect on nitric oxide production by J774A.1 macrophages of new anthraquinone derivatives. Med. Chem., 2013, 9(6), 812-818.
[] [PMID: 23072554]
Ashok, S.R.; Shivananda, M.K.; Manikandan, A.; Chandrasekaran, R. Discovery and synthesis of 2-amino-1-methyl-1H-imidazol-4(5H)-ones as GPCR ligands; an approach to develop breast cancer drugs via GPCR associated PAR1 and PI3Kinase inhibition mechanism. Bioorg. Chem., 2019, 86, 641-651.
[] [PMID: 30822721]
Kadirappa, A.; Manikandan, A.; Sailaja, R.M.; Napoleon, A.A. Copper-catalyzed quinoline derivatives evaluated as a new class of anticancer agents: Design, synthesis and molecular validations. J. Heterocycl. Chem., 2018, 55, 1669-1677.
Bosmann, M.; Ward, P.A. The inflammatory response in sepsis. Trends Immunol., 2013, 34(3), 129-136.
[] [PMID: 23036432]

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