Advertisement

Inflammopharmacology

, Volume 25, Issue 6, pp 621–631 | Cite as

Efficacy of phenyl quinoline phenol derivatives as COX-2 inhibitors; an approach to emergent the small molecules as the anti-inflammatory and analgesic therapeutics

  • A. Manikandan
  • S. Ravichandran
  • K. I. Sathiyanarayanan
  • A. SivakumarEmail author
Original Article

Abstract

2-(4-phenylquinoline-2-yl)phenol derivatives (4a-l) with COX-2 enzyme inhibition, analgesic, anti-inflammatory and antipyretic potentials were executed and reported. From the in vitro COX-2 enzyme inhibition assay, compounds 4 h (IC50 0.026 µM) and 4j (IC50 0.102 µM) were found as most potent COX-2 inhibitors. Consequently, to get more insight into the binding mode with COX-2, compounds 4a-l were docked into the COX-2 (PDB ID: 1CX2) active site. In the Human Red Blood Cells (HRBC) membrane stabilization assay (in vitro anti-inflammatory), compounds 4f (IC50 0.064 µM) substituted with –OH (R1) and –3Cl (R2), 4 h (IC50 0.021 µM), 4i (IC50 0.484 µg/ml) and 4j (IC50 0.092 µM) with –CHO containing alkanol and ether group at R1 and –4F, –4Br and –OMe at R2 (C2) were showed most potent anti-inflammatory activity. Eventually, acute toxicity studies revealed that 2-(4-phenylquinoline-2-yl)phenol derivatives (4a-l) are safe up to a toleration dose limit of 100 µg/kg body weight. In the Backer’s yeast intraperitoneal injection test, compounds 4f, 4 h and 4j produced significant (p < 0.05) antipyretic activity at 1, 1.5, 2 and 2.5 h, whereas test compound 4j and the reference drug indomethacin showed significant antipyretic activity throughout the observation period up to 2.5 h. Promising in vivo results obtained were correlated with the standard non-steroidal anti-inflammatory drugs and the compounds 4f, 4 h, 4i, 4j, and 4 l were efficiently identified as therapeutically potent/fortune moieties as non-steroidal anti-inflammatory agents/analgesics. At the end, ulcerogenic study result ensured that the tested 2-(4-phenylquinoline-2-yl)phenol derivatives created no side-effect.

Keywords

Anti-inflammatory COX-2 Analgesics Cytotoxicity IC50 Molecular docking NSAIAs 

Notes

Acknowledgements

The authors are grateful for the School of Bio-Science and Technology (SBST), VIT University for providing Research Associateship, necessary laboratory facilities and financial assistance (VIT SEED funding). Also thanking Mr. B.Umamahesh, School of Advanced Sciences, VIT University and Mr.V. Sadheeshkumar, Annamalai University, India for their immense help in the molecular synthesis and biological evaluations.

Supplementary material

10787_2017_342_MOESM1_ESM.pdf (3.2 mb)
Supplementary material 1 (PDF 3272 kb)

References

  1. Altman R, Bosch B, Brune K, Patrignani P, Young C (2015) Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology. Drugs 75:859–877CrossRefPubMedPubMedCentralGoogle Scholar
  2. Cai Z, Zhon W, Sun L (2007) Synthesis and HMG-CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents. Bioorg Med Chem 15:7809–7829CrossRefPubMedGoogle Scholar
  3. Chen Y, Chen J, Lu C, Tzeng C, Tsao H, Wang J (2003) Synthesis and anti-inflammatory evaluation of 9-phenoxyacridine and 4-phenoxyfuro [2,3-b] quinoline derivatives. Part 2. Bioorg Med Chem 11:3921–3927CrossRefPubMedGoogle Scholar
  4. Collier HO, Dinneen LC, Johnson CA, Schneider C (1968) The abdominal constriction response and its suppression by analgesic drugs in the mouse. Br J Pharmacol Chemother 32:295–310CrossRefPubMedPubMedCentralGoogle Scholar
  5. Copeland RA, Williams JM, Giannaras J, Nurnberg S, Covington M, Pinto D et al (1994) Mechanism of selective inhibition of the inducible isoforms of prostaglandin G/H synthase. Proc Natl Acad Sci 91:11202–11206CrossRefPubMedPubMedCentralGoogle Scholar
  6. Dannhardt G, Kiefer W (2001) Cyclooxygenase inhibitors-current status and future prospects. Eur J Med Chem 36:109–126CrossRefPubMedGoogle Scholar
  7. Eccles R (2006) Efficacy and safety of over-the-counter analgesics in the treatment of common cold and flu. J Clin Pharm Ther 31:309–319CrossRefPubMedGoogle Scholar
  8. El-Feky SA, El-Samii ZK, Osman NA, Lashine J, Kamel MA, Thabet HK (2015) Synthesis, molecular docking and anti-inflammatory screening of novel quinoline incorporated pyrazole derivatives using the Pfitzinger reaction II. Bioorganic chemistry 58:104–116CrossRefPubMedGoogle Scholar
  9. El-Gazzar AB, Youssef MM, Youssef AM, Abu-Hashem AA, Badria FA (2009) Design and synthesis of azolopyrimidoquinolines, pyrimidoquinazolines as anti-oxidant, anti-inflammatory and analgesic activities. Eur J Med Chem 44:609–624CrossRefPubMedGoogle Scholar
  10. Ferreira SH, Moncada S, Vane JR (1971) Indomethacin and aspirin abolish prostaglandin release from the spleen. Nat New Biol 231:237–239CrossRefPubMedGoogle Scholar
  11. Gaillard P, Carrupt PA, Testa B, Boudon A (1994) Molecular lipophilicity potential, a tool in 3D QSAR: method and applications. J Comput-Aided Mol Des 8(2):83–96CrossRefPubMedGoogle Scholar
  12. Ghosh J, Swarup V, Saxena A, Das S, Hazra A, Paira P, Banerjee S, Mondal NB, Basu A (2008) Therapeutic effect of a novel anilidoquinoline derivative, 2-(2-methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide, in Japanese encephalitis: correlation with in vitro neuroprotection. Int J Antimicrob Agents 32:349–356CrossRefPubMedGoogle Scholar
  13. Goodsell DS, Morris GM, Olson AJ (1996) Automated docking of flexible ligands: applications of AutoDock. J Molec Recognition 9:1–5CrossRefGoogle Scholar
  14. Hart FD, Boardman PL (1963) Indomethacin: a new non-steroid anti-inflammatory agent. Br Med J 2:965–970CrossRefPubMedPubMedCentralGoogle Scholar
  15. Huerre MR, Gounon P (1996) Inflammation: patterns and new concepts. Res Immunol 147:417–434CrossRefPubMedGoogle Scholar
  16. Janssen PA, Niemegeers CJ, Dony JG (1963) The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water induced tail withdrawal reflex in rats. Arzneimittelforschung 13:502–507PubMedGoogle Scholar
  17. Jimenez-Estrada M, Chilpa RR, Apan TR, Lledias F, Hansberg W, Arrieta D (2006) Anti-inflammatory activity of cacalol and cacalone sesquiterpenes isolated from Psacalium decompositum. J Ethnopharmacol 105:34–38CrossRefPubMedGoogle Scholar
  18. Jin HG, Sun XY, Chai KY, Piao HR, Quan ZS (2006) Anticonvulsant and toxicity evaluation of some 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones. Bioorg Med Chem 14:6868–6873CrossRefPubMedGoogle Scholar
  19. Kidwai M, Negi N (1997) Synthesis of some novel substituted quinolines as potent analgesic agents. Monatsh Chem 128:85–89CrossRefGoogle Scholar
  20. Lipnick RL, Cotruvo JA, Hill RN, Bruce RD, Stitzel KA, Walker AP et al (1995) Comparison of up-and-down, conventional LD50, and fixed dose acute toxicity procedures. Fd Chem Toxicol 33:223–231CrossRefGoogle Scholar
  21. Mahajan P, Nikam M, Asrondkar A, Bobade A, Gill C (2016) Synthesis, antioxidant, and anti-inflammatory evaluation of novel thiophene-fused quinoline-based β-diketones and derivatives. J Heterocyclic Chem 54:1415–1422CrossRefGoogle Scholar
  22. Małgorzata J, Eugenia IB, Maria P, Angeliki PK, Beata MM, Krystian P (2015) Synthesis of quinoline/naphthalene-containing azapheno thiazines and their potent in vitro antioxidant properties. Med Chem Res 24:1725–1732CrossRefGoogle Scholar
  23. Manikandan A, Sivakumar A (2016) Analgesic, anti-inflammatory and antipyretic evaluations of new Isoquinoline derivatives. Int J Pharm Pharm Sci 8:339–343Google Scholar
  24. Manikandan A, Sivakumar A (2017a) Molecular explorations of substituted 2-(4-phenylquinolin-2-yl) phenols as phosphoinositide3-kinase inhibitors and anticancer agents. Cancer Chemother Pharmacol 79:389–397CrossRefGoogle Scholar
  25. Manikandan A, Sivakumar A (2017b) 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 25:1448–1455CrossRefGoogle Scholar
  26. Manikandan A, Sathiyanarayanan KI, Sivakumar A (2015) Molecular docking, design, synthesis, in vitro antioxidant and anti-inflammatory evaluations of new isoquinoline derivatives. Int J Pharm Pharm Sci 7:200–208Google Scholar
  27. Manikandan A, Nemani SC, Sadheeshkumar V, Arumugam S (2016a) Spectroscopic investigations for photostability of diclofenac sodium complexed with hydroxypropyl-β-cyclodextrin. J App Pharm Sci 6:98–103CrossRefGoogle Scholar
  28. Manikandan A, Samuthirapandian R, Kumaravel K, Sivakumar A, Rethna P (2016b) Molecular docking and in vitro evaluations of Hippocampus trimaculatus (seahorse) extracts as anti-inflammatory compounds. Int J Bioinform Res Appl 12(4):355–371CrossRefGoogle Scholar
  29. Moriguchi I, Hirono S, Liu Q, Nakagome I, Matsushita Y (1992) Simple method of calculating octanol/water partition coefficients. Chem Pharm Bull 40:127–130CrossRefGoogle Scholar
  30. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 19:1639–1662CrossRefGoogle Scholar
  31. Mukherjee S, Pal M (2013) Medicinal chemistry of quinolines as emerging anti-inflammatory agents: an overview. Curr Med Chem 20(35):4386–4410CrossRefPubMedGoogle Scholar
  32. Mukherjee D, Nissen SE, Topol EJ (2001) The risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 286:954–959CrossRefPubMedGoogle Scholar
  33. Nandeshmanappa BP, Kumar DBA, Naik HSB, Mahadevan KM (2006) An efficient microwave-assisted synthesis of thieno [2, 3-b] quinolines under solvent-free conditions. J Sulfur Chem 26:373–379CrossRefGoogle Scholar
  34. OECD Publishing (2001) Acute oral toxicity-acute toxic class method. In: OECD Guideline for the testing of chemicals, Section 4: Health effects. 423 1-14Google Scholar
  35. Ong CKS, Lirk P, Tan CH, Seymour RA (2007) An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res 5(1):19–34. doi: 10.3121/cmr.2007.698 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Paiva LAF, Rao VSN, Gramosa NV, Silveira FR (1998) Gastroprotective effect of Copaifera langsdorffii oleo-resin on experimental gastric ulcer models in rats. J Ethnopharmacol 62:73–78CrossRefPubMedGoogle Scholar
  37. Patti R, Gumired K, Reddanna P (2002) Overexpression of cyclooxygenase-2 in human primitive neuroectodermal tumors: effect of celecoxib and rofecoxib. Cancer Lett 180:13–21CrossRefPubMedGoogle Scholar
  38. Petrovic N, Murray M (2010) Using N, N, N’, N’-tetramethyl-p-phenylenediamine (TMPD) to assay cyclooxygenase activity in vitro. Methods Mol Biol 594:129–140CrossRefPubMedGoogle Scholar
  39. Rajanarendar E, Nagi Reddy M, Rama Krishna S, Rama Murthy K, Reddy YN, Rajam MV (2012) Design, synthesis, antimicrobial, anti-inflammatory and analgesic activity of novel isoxazolyl pyrimido[4,5-b]quinolines and isoxazolyl chromeno[2,3-d]pyrimidin-4-ones. Eur J Med Chem 55:273–283CrossRefPubMedGoogle Scholar
  40. Roberts LJ, Morrow JD (2001) Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman JG Limbird LE (eds) The pharmacological basis of therapeutics. 10th edn. McGraw-Hill, New York, pp 687–732Google Scholar
  41. Sridhar P, Manikandan A, Sivakumar A, Sabbasani RR (2016) Synthesis of quinoline acetohydrazide-hydrazone derivatives evaluated as DNA gyrase inhibitors and potential antimicrobial agents. RSC Adv 6:64460–64468CrossRefGoogle Scholar
  42. Sridhar P, Manikandan A, Ram B, Sivakumar A, Reddy SR (2017) Drugs against neurodegenerative diseases: design and synthesis of 6-amino–substituted imidazo[1,2-b]pyridazines as acetylcholinesterase inhibitors. ChemistrySelect 2017(2):842–847CrossRefGoogle Scholar
  43. Teotino U, Friz LP, Gandini A, Bella DD (1963) Thio derivatives of 2, 3-dihydro-4H-1, 3-benzoxazin-4-one. Synthesis and pharmacological properties. J Med Chem 6:248–250CrossRefPubMedGoogle Scholar
  44. Umamahesh B, Sathiyanarayanan KI (2015) Synthesis and optical properties of a series of green-light-emitting 2-(4-phenylquinolin-2-yl)phenol–bf2 complexes (boroquinols). Eur J Org Chem 23:5089–5098Google Scholar
  45. Vane JR, Mitchell JA, Appleton I, Tomilison T, Bishop-Bailey D, Crontall J, Willoughby DA (1994) Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci 91:2046–2050CrossRefPubMedPubMedCentralGoogle Scholar
  46. Wada M, Saunders TL, Morrow J et al (2009) Two pathways for cyclooxygenase-2 protein degradation in vivo. J Biol Chem 284(45):30742–30753CrossRefPubMedPubMedCentralGoogle Scholar
  47. Xiang W-B, WangDa-Chuan L-HG, Zhe-Shan Q (2015) Synthesis and evaluation of the anti-inflammatory activity of quinoline derivatives. Med Chem Res 24:2591–2603CrossRefGoogle Scholar
  48. Zahradnik HP, Hanjalic-Beck A, Groth K (2010) Non-steroidal anti-inflammatory drugs and hormonal contraceptives for pain relief from dysmenorrhea: a review. Contraception 81:185–196CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.School of Bio-Science and TechnologyVIT UniversityVelloreIndia
  2. 2.Center of Advanced Study in Marine BiologyAnnamalai UniversityParangipettaiIndia
  3. 3.School Advanced SciencesVIT UniversityVelloreIndia

Personalised recommendations