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

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Abstract

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.

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References

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

  • Black, C, Grimm, E., Leger, S., and Wang, Z., Diaryl-5-Oxy- genated-2-(5H)-Furanones As COX-2 Inhibitors.WO Patent, 9636623 (1996b).

  • 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).

  • 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).

    Article  CAS  Google Scholar 

  • Bourassa, D. E., Castaldi, M. J., and Ripin, D. B., Process for preparing heterocyclo-alkysulfonyl pyrazole derivatives.US patent, 0100765 A1 (2003).

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Buck, J. S. and Ide, W. S., The isomeric desoxybenzanisoins.J. Am. Chem. Soc, 54, 3012–13 (1932).

    Article  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

  • Dannhardt, G. and Kiefer, W., Cyclooxygenase inhibitors - current status and future prospects.Eur. J. Med. Chem., 36, 109–26, (2001).

    Article  PubMed  CAS  Google Scholar 

  • Dannhardt, G. and Laufer, S., Cyclooxygenase inhibitors - current status and future prospectsCurr. Med. Chem., 7, 1101–1112 (2000).

    PubMed  CAS  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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 

  • Dube, D., Fortin, R., Friesen, R., Wang, Z., and Gauther, J. Y., Substituted pyridines as selective cyclooxygenase-2 inhibitors.US patent, 0065011 (2003).

  • Edvige,G T, John, K. D., Carol, R. D., and Brian, S. E., Novel Pyrrole derivatives.WO Patent, 9746524, (1997).

  • 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).

    Article  CAS  Google Scholar 

  • ]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).

  • 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).

    Article  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Kuntz, I. D., Dock, UCSF Box 2240, UCSF, San Fransico.

  • Kurogi, Y. and Guner, O. F., Pharmacophore modeling and threedimensional database searching for drug design using catalyst.Curr. Med. Chem., 8, 1035–1055 (2001).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Lo, C. P. and Shropshire, E. Y, Notes - Alkylation of 2,4- Thiazolidinedione.J. Org. Chem., 22, 999–1001 (1957).

    Article  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Lombardino, J. G., Non-Steroidal Anti-Inflammatory Drugs, Wiley, New York, pp. 255–431 (1985).

    Google Scholar 

  • 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).

    Article  Google Scholar 

  • 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).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Reddy, M. V. and Bell, S. C., Processes for the preparation of sustituted isoxazoles and 2-isoxazolines.US Patent, 0162813 A1 (2003).

  • Rosales, C. A., Gonzalez, C. G., and Barreda, M. C. T., Novel imidazole derivatives with anti-inflammatory activity.US patent, 0176481 A1 (2003).

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Sakya, S. M. and Rast, B., Heterocyclo-alkylsulfonyl pyrazoles as anti-inflammatory/analgesic agents.US patent, 0119836 A1 (2003).

  • Sakya, S. M., Shavnya A., and Rast, B., Sulfonyl aryl triazoles as anti-inflammatory/analgesic agents.US patent, 0125368 A1 (2003a).

  • Sakya, S. M., Shavnya A., and Rast, B., Sulfonyl heteroaryl triazoles as anti-inflammatory/analgesic agents.US patent, 0119835 A1 (2003b).

  • Seehra, J. S., Xiang, Y, Bemis, J. E., McKew, J., Kaila, N., and Chen, L, Inhibitors of phospholipase A2.WO Patent, 9943672 (1999a).

  • 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).

  • 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).

    CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • 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).

  • 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 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Vachal, P., Pihera, P., and Svoboda, J., Thieno[3,2-b]benzo- furan - Synthesis and Reactions.Collect. Czech. Chem. Commun., 62, 1468 (1997).

    Article  CAS  Google Scholar 

  • 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).

    Article  PubMed  CAS  Google Scholar 

  • Vane, J. R., Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.Nature-New biology, 231, 232-/235 (1971).

    PubMed  CAS  Google Scholar 

  • 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).

    Article  PubMed  Google Scholar 

  • 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).

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  1. Deptartment of medicinal chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt

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

  2. Deptartment of organic pharmaceutical chemistry, Faculty of Pharmacy, Assiut University, 71527, Assiut, Egypt

    Awwad A. Radwan

  3. Deptartment of pharmaceutical chemistry, Faculty of Pharmacy, Ain-Shams University, Cairo, Egypt

    Mohamed A. E. Hamid

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  1. Ahmed M. Ali
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Ali, A.M., Saber, G.E., Mahfouz, N.M. et al. Synthesis and three-dimensional qualitative structure selectivity relationship of 3,5-disubstituted-2,4-thiazolidinedione derivatives as COX2 inhibitors. Arch. Pharm. Res. 30, 1186–1204 (2007). https://doi.org/10.1007/BF02980259

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