Archives of Pharmacal Research

, Volume 30, Issue 10, pp 1186–1204 | Cite as

Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors

  • Ahmed M. Ali
  • Gamal E. Saber
  • Nadia M. Mahfouz
  • Mahmoud A. El-Gendy
  • Awwad A. Radwan
  • Mohamed A. E. Hamid


In our effort for synthesis of selective COX2 inhibitors, certain new 2,4-thiazolidinedione derivatives were synthesized. It necessitates preparation of potassium salt of 2,4-thiazolidinedione 2, which condensed with intermediate 4a. The resulting 3-[2-(4-methylphenyl)-2-oxo-1-phenylethyl]-2,4-thiazolidinedione 8 was condensed with appropriate aldehyde to afford compounds 10a, 10i-l, 10o and 10p. Compounds (9a-l, 10a-n, 10p, 11 and 12) were obtained through the preparation of 5-arylmethylidene-2,4-thiazolidinediones 6a-p and reaction of its potassium salt 7a-p with compounds 4a, 4b, and 5. Some compounds displayed significant analgesic activity as compared to reference standards. The anti-inflammatory activity of the synthesized compounds revealed that intermediate 8 and compounds 9c, 10c and 10d showed good results. Compound 10c produced no significant mucosal injury. HipHop methodology of Catalyst program was used to build up hypothetical model of selective COX2 inhibitors followed by fitting the synthesized compounds to this model. Compounds 10c and 10d were suspected to be promising selective COX2 inhibitors. Also, compounds (6c, 8, 9a,c,d,k, 10a,c,d,k, 11 and 12) were docked into COX1 and COX2 X-ray structures, using DOCK6 program. Docking results suggested that several of these derivatives are active COX inhibitors with a significant preference for COX2.

Key words

3D-QSSR 2,4-Thiazolidinediones COX2 inhibitors Catalyst Dock6 


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  1. Almansa, C, Alfon, J., de Arriba, A. F., Cavalcanti, F. L, Escamilla, I., Gomez, L. A., Miralles, A., Soliva, R., Bartroli, J., Carceller, E., Merlos, M., and Rafanell, J. G., Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.J. Med. Chem., 46, 3463–3475 (2003).PubMedCrossRefGoogle Scholar
  2. Anana, R., Praveen Rao, P. N., Qiao-Hong Chen, Q.-H., and Knaus, E. E., Synthesis and biological evaluation of linear phenylethynylbenzenesulfonamide regioisomers as cyclooxygenase- 1/-2 (COX-1/-2) inhibitors.Bioorg. Med. Chem., 14, 5259–5265, (2006).PubMedCrossRefGoogle Scholar
  3. Barnett, J. W., Dunn, J. P., Kertesz, D. J., Miller, A. B., Morgans, J. R., Ramesha, C. S., Sigal, C. E., Sjogren, E. B., Smith, D. B., and Talamas, F. X., Pyrrole derivatives.Eur. Patent, 0714895 (1996).Google Scholar
  4. Barnum, D., Greene, J., Smellie, A., and Sprague, P., Identification of common functional configurations among molecules.J. Chem. Inf. Comput. Sci., 36, 563–571 (1996).PubMedGoogle Scholar
  5. Bender, P. E., Hill, D. T., Offen, P. H., Razgaitis, K. A., Lavanchy, P., Stringer, O. D., Sutton, B. M., Griswold, D. E., DiMartino, M., Walz, D. T., Lantos, I., and Ladd, C. B., Inhibition of the 5- lipoxygenase pathway.J. Med. Chem., 28, 1169–1177 (1985).PubMedCrossRefGoogle Scholar
  6. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G, Bhat, T. N., Weissig, H., Shindyalov, I. N., and Bourne, P. E., The Protein Data Bank.Nucleic Acids Research, 28, 235–242 (2000).PubMedCrossRefGoogle Scholar
  7. Bernard, S. D., Arthur, A. D., Patrick, D. J., and Brian, S. E., 6- Benzyl-2H-pyridazin-3-one derivatives, their preparation and their use as inhibitors of prostaglandin G/H synthase I and II (COX I and COX II).Eur. Patent, 0810218 (1997).Google Scholar
  8. Black, C, Grimm, E., Leger, S., and Wang, Z., Diaryl-5-Oxy- genated-2-(5H)-Furanones As COX-2 Inhibitors.WO Patent, 9636623 (1996b).Google Scholar
  9. Black, C, Grimm, E., Leger, S., Prasit, P., and Wang, Z., Diaryl- 5-oxygenated-2-(5H)-furanones as COX-2 inhibitors.WO Patent, 9619469 (1996a).Google Scholar
  10. Boschelli, D. H., Conner, D. T., Kuipers, P. J., and Wright, C. D., Synthesis and cyclooxygenase and 5-lipoxygenase inhibitory activity of some thiazolidene-4-one analogs of meclofenamic acid.Bioorg. Med. Chem. Lett., 2, 705–708 (1992).CrossRefGoogle Scholar
  11. Bourassa, D. E., Castaldi, M. J., and Ripin, D. B., Process for preparing heterocyclo-alkysulfonyl pyrazole derivatives.US patent, 0100765 A1 (2003).Google Scholar
  12. Bruno, G, Costantino, L., Curinga, C., Maccari, R., Monforte, F., Nicolo, F., Ottana, R., and Vigorita, M. G., Synthesis and aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.Bioorg. Med. Chem., 10, 1077–1084, (2002.PubMedCrossRefGoogle Scholar
  13. Buck, J. S. and Ide, W. S., The isomeric desoxybenzanisoins.J. Am. Chem. Soc, 54, 3012–13 (1932).CrossRefGoogle Scholar
  14. Carabaza, A., Cabré, F., Rotllan, E., Goméz, M., Gutiérrez, M., Garcà, L., and Mauléon, D., A multicentre, randomised, double-blind study comparing the efficacy and tolerability of intramuscular dexketoprofen versus diclofenac in the symptomatic treatment of acute low back pain.J. Clin. Pharmacol., 36, 505–512, (1996).PubMedGoogle Scholar
  15. Cetenko, W. A, Connor, D. T., Sorenson, R. J., Unangst, P. C., and Stabler, S. R., Arylmethylenyl derivatives of thiazolidnones, imidazolidinones and oxazolidinones useful as antiallergy agents and anti-inflamatory agents.Eur. Pat., 0343643, (1989).Google Scholar
  16. Dannhardt, G. and Kiefer, W., Cyclooxygenase inhibitors - current status and future prospects.Eur. J. Med. Chem., 36, 109–26, (2001).PubMedCrossRefGoogle Scholar
  17. Dannhardt, G. and Laufer, S., Cyclooxygenase inhibitors - current status and future prospectsCurr. Med. Chem., 7, 1101–1112 (2000).PubMedGoogle Scholar
  18. Daveu, C., Bureau, R., Baglin, I., Prunier, H., Lancelot, J.-C., and Rault, S., Definition of a pharmacophore for partial agonist of serotonin 5-HT3 receptors.J. Chem. Inf. Comput. Sci., 39, 362–369(1999).PubMedGoogle Scholar
  19. De Levai, X., Julemont, F., Delarge, J., Pirotte, B., and Donge, J.-M., New trends in dual 5-LOX/COX inhibition.Curr. Med. Chem., 9, 941–962(2002).CrossRefGoogle Scholar
  20. De Lima, J. G, Perrissin, M., Chantegrel, J., Luu-Duc, C., and Narcisse, G., Synthesis and pharmacological evaluation of some 3-phenacyl-5-benzylidene-thiazolidine-2,4-diones.Arzneim-Forsch/Drug Res., 44, 831–834, (1994).Google Scholar
  21. Dube, D., Fortin, R., Friesen, R., Wang, Z., and Gauther, J. Y., Substituted pyridines as selective cyclooxygenase-2 inhibitors.US patent, 0065011 (2003).Google Scholar
  22. Edvige,G T, John, K. D., Carol, R. D., and Brian, S. E., Novel Pyrrole derivatives.WO Patent, 9746524, (1997).Google Scholar
  23. Fadl, T. A. and Omar, F. A. Paracetamol (acetaminophen) esters of some non-steroidal antiinflammatory carboxylic acids drugs as mutual prodrugs with improved therapeutic index.Inflammopharmacol., 6, 143–157 (1998).CrossRefGoogle Scholar
  24. ]Fred, B. and Frederick, G. M., The mechanism of indole formation from phenacylarylamines. Part III. The conditions and mechanism of the isomerisation and indolisation of phenacylarylamines.J. Chem. Soc., 858-870 (1948).Google Scholar
  25. Gauthier, J. Y, Leblanc, Y, Black, W. C., Chan, C.-C., Cromlish, W. A., Gordon, R., Kennedey, B. P., Lau, C. K., Leger, S., Wang, Z., Ethier, D., Guay, J., Mancini, J., Riedeau, D., Tagari, P., Vickers, P., Wong, E., Xu, L., and Prasit, P., Synthesis and biological evaluation of 2,3-diarylthiophenes as selective Cox-2 inhibitors-II. Replacing the heterocycle.Bioorg. Med. Chem. Lett., 6, 87–92 (1996).CrossRefGoogle Scholar
  26. Giles, R. G, Lewis, N. J., Quick, J. K., Sasse, M. J., Urquhart, M. W. J., and Youssef, L., Regiospecific reduction of 5- benzylidene-2,4-thiazolidinediones and 4-oxo-2-thiazolidinethiones using lithium borohydride in pyridine and tetrahydrofuran.Tetrahedron., 56, 4531–4537 (2000).CrossRefGoogle Scholar
  27. Greene, J., Kahn, S., Savoj, H., Sprague, P., and Teig, S., Chemical Function Queries for 3D Database Search.J. Chem. Inf. Comput Sci., 34, 1297–1308 (1994).Google Scholar
  28. Habeeb, A. G., Praveen Rao P. N., and Knaus, E. E., Design and synthesis of 4,5-Diphenyl-4-Isoxazolines: Novel inhibitors of cyclooxygenase-2 with analgesic and anti-inflammatory activityJ. Med. Chem., 44 2921–2927 (2001).PubMedCrossRefGoogle Scholar
  29. Hashimoto, H., Imamura, K., Haruta J., and Wakitani, K., 4-(4-Cycloalkyl/aryl-oxazol-5-yl)benzenesulfonamides as selective cyclooxygenase-2 inhibitors: Enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522.J. Med. Chem., 45, 1511–1517 (2002).PubMedCrossRefGoogle Scholar
  30. Hernandez-Perez, M., Rabanal, R. M., de La Torre, M. C., and Rodriguez, B., Analgesic, anti-inflammatory, antipyretic and haematological effects of aethiopinone, an o-naphthoquinone diterpenoid fromSalvia aethiopis roots and two hemisynthetic derivatives.Planta Med., 61, 505–509 (1995).PubMedCrossRefGoogle Scholar
  31. Hirashima, A., Pan, C., Kuwano, E., Taniguchi, E., and Eto, M., Three-dimensional pharmacophore hypotheses for the locust neuronal octopamine receptor (OAR3). Part 2: agonists.Bioorg. Med. Chem., 7, 1437–1443, (1999).PubMedCrossRefGoogle Scholar
  32. Kiefer, J. R., Pawlitz, J. L, Moreland, K. T., Stegeman, R. A., Hood, W. F., Gierse, J. K., Stevens, A. M., Goodwin, D. C, Rowlinson, S. W., Marnett, L. J., Stallings, W. C, and Kurumbail, R. G., Structural insights into the stereochemistry of the cyclooxygenase reaction.Nature, 405, 97–101 (2000).PubMedCrossRefGoogle Scholar
  33. Kuntz, I. D., Dock, UCSF Box 2240, UCSF, San Fransico.Google Scholar
  34. Kurogi, Y. and Guner, O. F., Pharmacophore modeling and threedimensional database searching for drug design using catalyst.Curr. Med. Chem., 8, 1035–1055 (2001).PubMedGoogle Scholar
  35. Kurumbail, R. G, Stevens, A. M., Gierse, J. K., McDonald, J. J., Stegeman, R. A., Pak, J. Y, Gildehaus, D., Miyashiro, J. M., Penning, T. D., Seibert, K., Isakson, P. C., Stallings, W. C., Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents.Nature, 384, 644–648, (1996).PubMedCrossRefGoogle Scholar
  36. Lantos, I., Bender, P. E., Razgaitis, K. A., Sutton, B. M., DiMartino, M. J., Griswold, D. E., and Walz, D. T., Anti-inflammatory activity of 5,6-diaryl-2,3-dihydroimidazo[2,1-b]thiazoles. Isomeric 4-pyridyl and 4-substituted-phenyl derivatives.J. Med. Chem., 27 72–75, (1984).PubMedCrossRefGoogle Scholar
  37. Li, C. S., Brideau, C., Chan, C. C., Savoie, C., Claveau, D., Charieson, S., Gordon, R., Greig, G., Gauthier, J. Y., Lau, C. K., Riendeau, D., Therien, M., Wong, E., and Pasit, P., Pyridazinones as selective cyclooxygenase-2 inhibitors.Bioorg. Med. Chem. Lett., 13, 597–600 (2003).PubMedCrossRefGoogle Scholar
  38. Lo, C. P. and Shropshire, E. Y, Notes - Alkylation of 2,4- Thiazolidinedione.J. Org. Chem., 22, 999–1001 (1957).CrossRefGoogle Scholar
  39. Lo, C. P., Shropshire, E. Y., and Croxall, W. J., 5-Aralylidine-3- isobutyl-2,4-thiazolidinediones.J. Am. Chem. Soc., 75, 4845- 4846(1953).CrossRefGoogle Scholar
  40. Lohray, B. B., Bhushan, V, Reddy, A. S., Rao, P. B., Reddy, N. J., Harikishore, P., Haritha, N., Vikramadityan, P. K., Chakrabarti, R., Rajagopalan, R., and Katneni, K., Novel euglycemic and hypolipidemic agents. 4. pyridyl- and quinolinyl-containing thiazolidinediones.J. Med. Chem., 42, 2569–81 (1999).PubMedCrossRefGoogle Scholar
  41. Lombardino, J. G., Non-Steroidal Anti-Inflammatory Drugs, Wiley, New York, pp. 255–431 (1985).Google Scholar
  42. Naser, M. N. A. and Said, S. A., Novel 3, 3a, 4, 5, 6, 7- hexahydroindazole and arylthiazolylpyrazoline derivatives as anti-inflammatory agents.Arch. Pharm. Pharm. Med. Chem., 336, 551–559 (2003).CrossRefGoogle Scholar
  43. Nojima, H., Tsuneki, H., Kimura, I., and Kimura, M., Accelerated desensitization of nicotinic receptor channels and its dependence on extracellular calcium in isolated skeletal muscles of streptozotocin-diabetic mice.Br. J. Pharmacol., 116, 1680–1684 (1995).PubMedGoogle Scholar
  44. Omar, F. A., Mahfouz, N. M., and Fadl, T. A., Design, synthesis and anti-inflammatory activity of some 1,3,4-oxadiazole derivatives.Eur. J. Med. Chem., 31, 819–825 (1996).CrossRefGoogle Scholar
  45. Pal, M., Madan, M., Padakanti, S., Pattabiraman, V. R., Kalleda, S., Vanguri, A., Mullangi, R., Rao Mamidi, N. V. S., Casturi, S. R., Malde, A., Gopalakrishnan, B., and Yeleswarapu, K. R., Synthesis and cyclooxygenase-2 inhibiting property of 1,5- diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: preparation of sodium salt for injectable formulation.J. Med. Chem., 46, 3975–3984 (2003).PubMedCrossRefGoogle Scholar
  46. Palomer, A, Cabre, F., Pascual, J., Campos, J., Trujillo, M. A., Entrena, A., Gallo, M. A., Garcia, L., Mauleon, D., and Esponosa, A., Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models.J. Med. Chem., 45, 1402–1411 (2002).PubMedCrossRefGoogle Scholar
  47. Picot, D., Loll, P. J., and Garavito, R. M., The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.Nature, 367, 243–249 (1994).PubMedCrossRefGoogle Scholar
  48. Portevin, B., Tordjman, C., Pastoureau, P., Bonnet, J., and De Nanteuil, G, 1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole Derivatives: A new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite.J. Med. Chem., 43, 4582–4593 (2000).PubMedCrossRefGoogle Scholar
  49. Reddy, M. V. and Bell, S. C., Processes for the preparation of sustituted isoxazoles and 2-isoxazolines.US Patent, 0162813 A1 (2003).Google Scholar
  50. Rosales, C. A., Gonzalez, C. G., and Barreda, M. C. T., Novel imidazole derivatives with anti-inflammatory activity.US patent, 0176481 A1 (2003).Google Scholar
  51. Rowlinson, S. W., Kiefer, J. R., Prusakiewicz, J. J., Pawlitz, J. L., Kozak, K. R., Kalgutkar, A. S., Stallings, W. C, Kurumbail, R. G, and Marnett, L. J., A novel mechanism of cyclooxygenase-2 inhibition involving interactions with Ser-530 and Tyr-385.J. Biol. Chem., 278, 45763–45769 (2003).PubMedCrossRefGoogle Scholar
  52. Sakya, S. M. and Rast, B., Heterocyclo-alkylsulfonyl pyrazoles as anti-inflammatory/analgesic agents.US patent, 0119836 A1 (2003).Google Scholar
  53. Sakya, S. M., Shavnya A., and Rast, B., Sulfonyl aryl triazoles as anti-inflammatory/analgesic agents.US patent, 0125368 A1 (2003a).Google Scholar
  54. Sakya, S. M., Shavnya A., and Rast, B., Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic agents.US patent, 0119835 A1 (2003b).Google Scholar
  55. Seehra, J. S., Xiang, Y, Bemis, J. E., McKew, J., Kaila, N., and Chen, L, Inhibitors of phospholipase A2.WO Patent, 9943672 (1999a).Google Scholar
  56. Seehra, J. S., McKew, J., Lovering, F., Bemis, J. E, Xiang, Y, Chen, L, and Knopf, J. L, Inhibitors ofphospholipas enzymes.WO Patent, 9943654 (1999b).Google Scholar
  57. Shevchuk, M. I. and Dombrovskii, A. V., Preparation of α- monobromomethyl aryl ketones by bromination of methyl aryl ketones in dioxane.Zhur. Obshch. Khim. 1963, 33, 1135–1136; through Chem. Abstr., 59, 9921g (1963).Google Scholar
  58. Sui, Z., Guan, J., Ferro, M. P., McCoy, K., Wachter, M. P., Murray, W. V, Singer, M., Steber, M., Ritchie, D. M., and Argentieri, D. C., 1,3-Diarylcycloalkanopyrazoles and diphenyl hydrazides as selective inhibitors of cyclooxygenase-2.Bioorg. Med. Chem. Lett., 10, 601–604 (2000).PubMedCrossRefGoogle Scholar
  59. Talley, J. J., Brown, D. L, Nagarajan, S., Carter, J. S., Weier, R. M., Stealey, R. M., Collins, P. W., Roland, R. D., and Karen, S., Substituted isoxazoles for the treatment of inflammation.US patent, 5633272 (1997).Google Scholar
  60. Turkevich, N. M., Vvedenskii, V. M., and Petlich-naya, L. M., Substitution in the azolidine rign. Method of obtaining pseudothiohydantoin and 2,4-thiazolidinedione.Ukr. Khim. Zh, 1961, 27, 680-81; through Chem. Abstr., 56, 14254e (1962).Google Scholar
  61. Unangst, P. C., Conner, D. T., Cetenko, W. A., Sorenson, R. J., Kostlan, C. R., Sircar, J. C., Wright, C. D., Schrier, D. J., and Dyer, R. D., Synthesis and biological evaluation of 5-[[3,5- bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]oxazoles, -thiazoles, and -imidazoles: novel dual 5-lipoxygenase and cyclooxygenase inhibitors with antiinflammatory activity.J. Med. Chem., 37, 322–28 (1994).PubMedCrossRefGoogle Scholar
  62. Vachal, P., Pihera, P., and Svoboda, J., Thieno[3,2-b]benzo- furan - Synthesis and Reactions.Collect. Czech. Chem. Commun., 62, 1468 (1997).CrossRefGoogle Scholar
  63. Valencia, E., Feria, M., Diaz, J. G, Gonzalez, A., and Bermejo, J., Antinociceptive, anti-inflammatory and antipyretic effects of lapidin, a bicyclic sesqiterpene.Planta Med., 60, 395–99 (1994).PubMedCrossRefGoogle Scholar
  64. Vane, J. R., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature-New biology, 231, 232-/235 (1971).PubMedGoogle Scholar
  65. Velázquez, C., Praveen Rao, P. N., McDonald, R., and Knaus, E. E., Synthesis and biological evaluation of 3,4-diphenyl- 1,2,5-oxadiazole-2-oxides and 3,4-diphenyl-1,2,5-oxadiazoles as potential hybrid COX-2 inhibitor/nitric oxide donor agents.Bioorg. Med. Chem., 13, 2749–57 (2005).PubMedCrossRefGoogle Scholar
  66. Ward, A. M., Investigations on the bivalency of carbon. Part II. The displacement of chlorine from desyl chloride. Benzoin diethylacetal.J. Chem. Soc., 1541-1553 (1929).Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2007

Authors and Affiliations

  • Ahmed M. Ali
    • 1
  • Gamal E. Saber
    • 1
  • Nadia M. Mahfouz
    • 1
  • Mahmoud A. El-Gendy
    • 1
  • Awwad A. Radwan
    • 1
    • 2
  • Mohamed A. E. Hamid
    • 1
    • 3
  1. 1.Deptartment of medicinal chemistry, Faculty of PharmacyAssiut UniversityAssiutEgypt
  2. 2.Deptartment of organic pharmaceutical chemistry, Faculty of PharmacyAssiut UniversityAssiutEgypt
  3. 3.Deptartment of pharmaceutical chemistry, Faculty of PharmacyAin-Shams UniversityCairoEgypt

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