Abstract
Simulation of virtually designed 20 compounds as COX-2 inhibitors using molecular modelling of protein–ligand interactions to predict drug structure–activity relationship was performed in this study. A synthetic route with a rational chemical approach to (E)-2-oxo-(thio)-4-substituted phenyl-6-styryl-1,2,3,4-tetrahydro-pyrimidine-5-caboxylic acid was designed and demonstrated. A comparative analysis of antimetabolite drug and corresponding metabolites (virtually designed compounds) provided a better understanding of rational drug design. COX-1(pdb entry: 1eqg) and COX-2(pdb entry: 6cox) enzymes docked with novel ligands were evaluated for binding energies. Lead optimization was performed by computational simulation: methoxy-substituted analogues displayed the highest negative ligand–protein-binding energies. These results prompted us to evaluate in vivo anti-inflammatory activity by carrageenan-induced paw oedema test in rats at a dose of 100 mg/kg. Ibuprofen was administered as standard drug. Lead compounds having significant activity were tested for in vitro cyclooxygenase isoenzyme inhibition assay and found to be more selective towards COX-2 as indicated by COX-2 selective index. The objective of our research is to accept the challenge of discovery of new drug. To ensure the desired target specificity and potency, bioavailability and lack of toxicity, our approach stems out lead generation from virtual screening to their synthesis and ends up with biological assays.
Similar content being viewed by others
References
Agarwal SK, Tadiparthi R, Aggarwal P, Shivakumar S (2003) PCT Int. Appl. WO 2003084936, Chem Abstr 139: 323529
Argus Lab 4.0.1 docking software (2010). http://www.arguslab.coms. Accessed May 2011
Atwal KS, Rovnyak GC, O’Reilly BC, Schwartz J (1989) Substituted 1,4 dihydropyrimidines. Synthesis of selectively functionalised 2-hetero 1,4 dihydropyrimidines. J Org Chem 54:5898
Atwal KS, Swanson BN, Unger SE, Floyd DM, Morel S, Hedberg A, O’Reilly BC (1991) Dihydropyrimidine calcium channel blockers. 3.3-Carbamoyl-4-aryl-1,2,3,4 tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents. J Med Chem 34:806–811
Bahekar SS, Shinde DB (2003) Synthesis and anti-inflammatory activity of some [2-amino-6-(4-substituted aryl)-4-(4-substituted phenyl)-1,6-dihydropyrimidine-5-yl] acetic acid derivatives. Acta Pharm 53:223–229
Bhattacharyya DK, Lecomte M, Rieke CJ, Garavito MR, Smith WL (1996) The role of arginine120 of human prostaglandin endoperoxide H synthase-2 in the interaction with fatty acid substrates and inhibitors. J Biol Chem 271:2179
Biginelli P (1893) The urea–aldehyde derivatives of actiacetic esters. Gazz Chim Ital 23:360–416
Bruno O, Brullo C, Ranise A, Schenone S, BondAvalls S, Barocelli E, Ballabeni V, Chiavarini M, Tognolini M, Impicciatore M (2001) Synthesis and pharmacological evaluation of 2,5-cycloamino-5H-[1]benzopyrano[4,3-d] pyrimidines endowed with in vitro antiplatelet activity. Bioorg Med Chem Lett 11:1397
Carter MC, Naylor A, Payne JJ, Pegg NA (2003) PCT Int. Appl. WO 2003014091 Chem Abstr 138:187783
Clare M, Hagen TJ, Houdek SC, Lennon PJ, Weier RM, Xu X (2005) PCT Int. Appl. WO 2005040133 Chem Abstr 142: 463736
Chemdraw 3D Ultra software (2008). Accessed May 2011 www.cambridgesoft.com
Dannhart G, Kiefer W (2001) Cyclooxygenase inhibitors—current status and future prospects. Eur J Med Chem 36:109–126
Prasit P, Wang Z, Brideau CC, Chan S, Charleson S, Cromlish W, Ethier D, Ford- Hutchinson, JFA, Evans W, Gauthier JY, Gordon R, Guay J, Kargman M,Gresser S, Kennedy B, Leblanc Y, Leger S P, Mancini GP, O’Neill, Ouellet M, Percival MD, Perrier H, Riendeau D, Rodger, Tagari P, M′rien The, Vickers P, Wong E, Xu LJ, Young RN, Zamboni R (1999) The discovery of rofecoxib [MK 966,VIOXX-4-(4′-methyls ulfo nyl phenyl)-3-p-phenyl-2(5H)-furan one)] an orally active cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett 9: 1773–1779
Franklin AS, Ly SK, Mackin GH, Overman LE, Shaka AJ (1999) Application of the tethered biginelli reaction for enantioselective synthesis of batzelladine alkaloids. Absolute configuration of the tricyclic guanidine portion of batzelladine. J Org Chem 64:1512–1519
Greig GM, Francis DA, Falgueyret J-P, Ouellet M, Percival MD, Roy P, Bayly C, Mancini JA, O’Neill GP (1997) The interaction of arginine106 of human prostaglandin G/H synthase-2 with inhibitors is not a universal component of inhibition mediated by nonsteroidal anti-inflammatory drugs. Mol Pharmacol 52:829–838
Hill MR, Holland SJ, Pearson SL, Yeates KT (2004) PCT Int. Appl. WO 2004048344 Chem Abstr 141:38626
Kalgutkar A, Marnett AB, Crews B, Remmel RP, Marnett LJ (2000) Ester and amide drivatives of nonstereroidal anti-inflammatory drugs, indomethacin, as selective cyclooxygenase-2 inhibitors. J Med Chem 43:2860–2870
Kappe CO (1993) 100 years of the Biginelli dihydropyrimidine synthesis. Tetrahedron 49:6937–6963
Kappe CO (2000) Biologically active dihydropyrimidones of the Biginelli-type—a literature survey. Eur J Med Chem 35:1043–1052
Kurumbail RG, Stevens AM, Gierse JK, McDonald J, Stegeman RA (1996) Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature 384:644–648
Liu L, Lopez, Bajpai M, Siegmund AC (2005) U.S. Pat. Appl. Publ. US 2004-923067 Chem Abstr 142261550
Loll PJ, Picot D, Garavito RM (1995) The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase. Nature Struct Biol 2:637
Loll PJ, Picot D, Ekabo O, Garavito RM (1996) Synthesis and use of iodinated non steroidal anti-inflammatory drug analogs as crystallographic probes of prostaglandin H2 synthase cyclooxygenase. Biochemistry 35:7330
Lozano JJ, Pouplana R, Ruiz J (1997) Molecular electrostatic potential in differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) by non-steroidal antiinflammatory drug. J Mol Struct (Theochem) 397:59
Mokale SN, Shinde SS, Elgire RD, Sangshetti JN, Shinde DB (2010) Synthesis and anti- inflammatory activity of some 3-(4,6-disubtituted-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl) propanoic acid derivatives. Bioorg Med Chem Lett 20:4424–4426
Moreau A, Chen QH, Praveen Rao PN, Knaus EE (2006) Design, synthesis and biological evaluation of (E)-3-(4-methanesulfonylphenyl)-2-(aryl)acrylic acids as dual inhibitors of cyclooxygenases and lipoxygenases. Bioorg Med Chem 14:7716–7727
Mukinsty DW, Reading EH (1994) Derivatives on experimental murine poliomyelitis Studies on the chemotherapy of experimental virus infections. The effect of certain pyrimidine. J Frankl Inst 237:422
Ouellet M, Percival D (1995) Effect of inhibitor time-dependency on selectivity towards cyclooxygenase isoforms. Biochem J 306:247
Picot D, Loll PJ, Garavito RM (1994) The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1. Nature 367:243
Pouplana R, Pérez C, Sánchez J, Lozano JJ, Puig-Parellada P (1999) The structural and electronical factors that contribute affinity for the time-dependent inhibition of PGHS-1 by indomethacin, diclofenac and fenamates. J Comput Aided Mol Des 13:297
Selinsky BS, Gupta K, Sharkey CT, Loll PJ (2001) Structural analysis of NSAID binding by prostaglandin H2 synthase: time-dependent and time-independent inhibitors elicit identical enzyme conformations. Biochemistry 40:5172–5180
Shutalev AD, Aksionov AN (2005) Simple synthesis of 4-aryl-6-styryl-1,2,3,4 tetrahydropyrimidin-2-ones by alkaline hydrolysis of Biginelli compound. Mendeleev Commun 15:73–75
Sondhi SM, Goyal RN, Lahoti AM, Singh N, Shukla R, Raghubir R (2005) Synthesis and biological evaluation of 2-thiopyrimidine derivatives. Bioorg Med Chem 13:3185
Steel TG, Coburn CA, Patane MA, Bock MG (1998) Expedient synthesis of 5-unsubstituted 3,4 dihyropyrimidin-2(1H)-ones. Tetrahedron Lett 39:9315–9318
Uddin MJ, Praveen Rao PN, Knaus EE (2004) Design and synthesis of acyclic triaryl (Z) olefins: a novel class of cyclooxygenase (COX-2) inhibitors. Bioorg Med Chem 12:5929–5940
Wang Renxiao, Fang Xueliang, Yipin Lu (2004) The PDB bind database: collection of binding affinities for protein–ligand complexes with known three dimensional structures. J Med Chem 47:2977–2980
Winter CA, Risley EA, Nuss GW (1962) Carrageenin induced oedema in hind paw of the rat as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–554
Zigeuner G, Knopp C, Blaschke H (1976) Tetrahydro-6-methyl and -6-phenyl-2-oxopyrimidin-5-carboxylic acids and derivatives. Monatsh Chem 107:587–603
Acknowledgments
RPD is grateful to the UGC, New Delhi for financial assistance under Faculty Improvement Program of XI plan. The authors are thankful to the SAIF, Chandigarh for 1HNMR, 13CNMR, CHN, Mass spectral analysis and also thankful to the Department of Pharmacy, Nagpur for IR spectral analysis. The authors also thank the Director, Institute of Science, Nagpur for providing lab facilities, and the CDRI Lucknow for in vivo anti-inflammatory activity.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Dhankar, R., Rahatgaonkar, A.M., Shukla, R. et al. Computer simulation of the in vitro and in vivo anti-inflammatory activities of dihydropyrimidines acid derivatives through the inhibition of cyclooxygenase-2. Med Chem Res 22, 2493–2504 (2013). https://doi.org/10.1007/s00044-012-0244-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-012-0244-2