P. Eleftheriou et al. / European Journal of Medicinal Chemistry 47 (2012) 111e124
123
[25] Y. Cao, T. Jiang, T. Girke, A maximum common substructure-based algorithm
for searching and predicting drug-like compounds, Bioinformatics 24 (2008)
366e374.
(hydrophobic) interactions governing binding disparities among
the series of these compounds.
[26] J. Masciocchi, G. Frau1, M. Fanton, M. Sturlese, M. Floris, L. Pireddu, P. Palla,
F. Cedrati, P. Rodriguez-Tome, S. Moro, MMsINC:
a large-scale chemo-
Appendix. Supplementary data
informatics database, Nucleic Acids Res. 37 (2009) 284e290.
[27] Q.S. Du, R.B. Huang, Y.T. Wei, Z.W. Pang, L.Q. Du, K.C. Chou, Fragment-based
quantitative structure-activity relationship (FB-QSAR) for fragment-based
drug design, J. Comput. Chem. 30 (2009) 295e304.
[28] B.M. Spowage, C.L. Bruce, J.D. Hirst, Interpretable correlation descriptors for
quantitative structureeactivity relationships, J. Cheminf. 1 (2009).
[29] M.A.C. Pérez, M.B. Sanz, L.R. Torres, R.G. Ávalos, M. Pérez González,
H. González Díaz, A topological sub-structural approach for predicting human
intestinal absorption of drugs, Eur. J. Med. Chem. 39 (2004) 905e916.
[30] D. Livingstone, Data Analysis for Chemists. Oxford University Press, Oxford,
1995.
Supplementary data associated with this article can be found, in
References
[1] C. Melchiorre, M.L. Bolognesi, A. Minarini, M. Rosini, V. Tumiatti, Polyamines
in drug discovery: from the universal template approach to the multitarget-
directed ligand design strategy, J. Med. Chem. 53 (2010) 5906e5914.
[2] R. Morphy, Z. Rankovic, Designed multiple ligands. An emerging drug
discovery paradigm, J. Med. Chem. 48 (2005) 6523e6543.
[31] D.A. Filimonov, V.V. Poroikov, Probabilistic approach in activity prediction. in:
A. Varnek, A. Tropsha (Eds.), Chemoinformatics Approaches to Virtual
Screening. RSC Publishing, Cambridge (UK), 2008, pp. 182e216.
[32] A. Geronikaki, D. Druzhilovsky, A. Zakharov, V. Poroikov, Computer-aided
predictions for medicinal chemistry via Internet, SAR QSAR Environ. Res. 19
(2008) 27e38.
[33] A.A. Lagunin, O.A. Gomazkov, D.A. Filimonov, T.A. Gureeva, E.A. Dilakyan,
E.V. Kugaevskaya, Y.E. Elisseeva, N.I. Solovyeva, V.V. Poroikov, Computer-
aided selection of potential antihypertensive compounds with dual mecha-
nisms of action, J. Med. Chem. 46 (2003) 3326e3332.
[34] X.Q. Lewell, D.B. Judd, S.P. Watson, M.M. Hann, RECAPeretrosynthetic
combinatorial analysis procedure: a powerful new technique for identifying
privileged molecular fragments with useful applications in combinatorial
chemistry, J. Chem. Inf. Comput. Sci. 38 (3) (1998) 511e522.
[35] J. Degen, M. Rarey, FlexNovo: structure-based searching in large fragment
spaces, Chem. Med. Chem. 1 (2006) 854e868.
[3] C. Wermuth, Multitargeted drugs: the end of the “one-target-one disease”
philosophy? Drug Disc. Today 9 (2004) 826e827.
[4] P. Csermely, V. Agoston, S. Pongor, The efficiency of multi-target drugs: the
network approach might help drug design, Trends Pharmacol. Sci. 26 (2005)
178e182.
[5] J. Lehar, A.S. Krueger, W. Avery, A.M. Heilbut, L.M. Johansen, E.R. Price,
R.J. Rickles, G.F. Short, J.E. Staunton, X. Jin, M.S. Lee, G.R. Zimmermann,
A.A. Borisy, Synergistic drug combinations tend to improve therapeutically
relevant selectivity, Nat. Biotechnol. 27 (2009) 659e666.
[6] J. Rodon, J. Perez, R. Kurzrock, Combining targeted therapies: practical issues
to consider at the bench and bedside, Oncologist 15 (2010) 37e50.
[7] J. Minnerup, W.-R. Schabitz, Multifunctional actions of approved and candi-
date stroke drugs, Neurotherapeutics 6 (2009) 43e52.
[36] D. Douguet, H. Munier-Lehmann, G. Labesse, S. Pochet, LEA3D: a computer-aided
liganddesignforstructure-baseddrugdesign,J. Med. Chem.48(2005)2457e2468.
[37] C.A. Nicolaou, J. Apostolakis, C.S. Pattichis, De novo drug design using multi-
objective evolutionary graphs, J. Chem. Inf. Model. 49 (2009) 295e307.
[38] A.S. Tarendash, Let’s Review Chemistry, the Physical Setting, fourth ed. Bar-
ron’s Educational Series, New York, 2006, 228e242.
[8] M.J. Milan, Dual- and triple-acting agents for treatment core and co-morbid
symptoms of major depression: novel concepts, new drugs, Neuro-
therapeutics 6 (2009) 53e77.
[9] C.R. Rodrigues, M.P. Veloso, H. Verli, C.A. Fraga, A.L. Miranda, E.J. Barreiro,
Selective PGHS-2 inhibitors:
a rational approach for treatment of the
inflammation, Curr. Med. Chem. 9 (2002) 849e867.
[39] P.S. Kutchukian, E.I. Shakhnovich, De novo design: balancing novelty and
confined chemical space, Expert Opin. Drug Discov. 5 (2010) 789e812.
[40] P. Vicini, A. Geronikaki, M. Incerti, F. Zani, J.C. Dearden, M. Hewitt, Hetero-
arylimino-5-benzylidene-4-thiazolidinones analogues of 2-thiazolylimino-5-
benzylidene-4-thiazolidinones with antimicrobial activity: synthesis and
structureeactivity relationship, Bioorg. Med. Chem. 16 (7) (2008) 3714e3724.
[41] P. Vicini, A. Geronikaki, A. Kitka, M. Incerti, F. Zani, Synthesis and antimicrobial
activity of novel 2-thiazolylimino-5-arylidene-4-thiazolidinones, Bioorg. Med.
Chem. 14 (2006) 3859e3864.
[10] R. Ottana, R. Maccari, M.T. Barreca, G. Bruno, A. Rotondo, A. Rossi,
G. Chiricosta, R. Paola, L. Sautebin, S. Cuzzocrea, M.G. Vigorita, 5-Arylidene-2-
imino-4-thiazolidinones: design and synthesis of novel anti-inflammatory
agents, Bioorg.Med. Chem. 13 (2005) 4243e4252.
[11] T.D. Venu, S. Shashikanth, S.A. Khanum, S. Naveen, A. Firdouse, M.A. Sridhar,
J.S. Prasad, Synthesis and crystallographic analysis of benzophenone deriva-
tivesdthe potential anti-inflammatory agents, Bioorg. Med.Chem. 15 (2007)
3505e3514.
[12] X. Leval, F. Julémont, J. Delarge, B. Pirotte, J.-M. Dogné, New trends in dual 5-
LOX/COX inhibition, Curr. Med. Chem. 9 (2002) 941e962.
[42] A. Geronikaki, G. Theophilidis, Synthesis of 2-(aminoacetylamino)thiazole
derivatives and comparison of their local anaesthetic activity by method of
action potential, Eur. J. Med. Chem. 27 (1992) 709e716.
[13] J.F. Penrose, K.F. Austen, B.K. Lam, Leukotrienes: biosynthetic pathways,
release and receptor-mediated actions with relevance to disease states. in:
J.L. Gallin, R. Snyderman (Eds.), Inflammation Basic Principles and Clinical
Correlates. Lippicort Williams & Wilkins, Philadelphia, 1999, pp. 361e372.
[14] J.R. Vane, Y.S. Bakhle, R.M. Botting, Cyclooxygenases 1 and 2, Annu. Rev.
Pharmacol. Toxicol. 38 (1998) 97e120.
[15] J. Martel-Pelletier, D. Lajeunesse, P. Reboul, J.-P. Pelletier, Therapeutic role of
dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal
anti-inflammatory drugs, Ann. Rheum. Dis. 62 (2003) 501e509.
[16] J.Y. Jouzeau, B. Terlain, A. Abid, E. Nedelec, P. Netter, Cyclo-oxygenase isoen-
zymes. How recent findings affect thinking about nonsteroidal anti-
inflammatory drugs, Drugs 53 (1997) 563e582.
[43] C. Papadopoulou, A. Geronikaki, D. Hadjipavlou-Litina, Synthesis and biolog-
ical evaluation of new thiazolyl/benzothiazolyl-amides, derivatives of 4-
phenyl-piperazine, Farmaco 60 (2005) 969e973.
ꢀ
ꢀ
ꢀ
ꢁ
[44] O. Kouatli, P. Zoumpoulakis, Ch. Camoutsis, M. Sokovic, A. Ciric, J. Glamoclija,
A. Geronikaki, Novel 4-thiazolidinone derivatives as potential antifungal and
antibacterial drugs, Bioorg. Med. Chem. 18 (2010) 426e432.
[45] GOLD, Version 2.2; Cambridge Crystallographic Data Centre: Cambridge, UK.
[46] D. Picot, P.J. Loll, R.M. Garavito, The X-ray crystal structure of the membrane
protein prostaglandin H2 synthase-1, Nature 367 (1994) 243e249.
[47] S. Mittal, A. Malde, C. Selvam, K.S. Arun, P.S. Johar, S.M. Jachak, P. Ramarao,
P.V. Bharatam, H.P.S. Chawla, Synthesis and evaluation of S-4-(3-thienyl)
[17] M. Bayes, X. Rabasseda, J.R. Prous, Gateways to clinical trials, Methods Find.
Exp. Clin. Pharmacol. 24 (8) (2002) 525e551.
phenyl-
a-methylacetic acid, Bioorg. Med. Chem. Lett. 14 (2004) 979e982.
[48] M. Lindner, W. Sippl, A. Radwan, Pharmacophore Elucidation and molecular
docking studies on 5-phenyl-1-(3-pyridyl)-1H-1,2,4-triazole-3-carboxylic
acid derivatives as COX-2 inhibitors, Sci. Pharm. 78 (2010) 195e214.
[49] Md. J. Uddin, P.N. Praveen Rao, E.E. Knaus, Design of acyclic triaryl olefins:
a new class of potent and selective cyclooxygenase-2 (COX-2) inhibitors,
Bioorg. Med. Chem. Lett. 14 (2004) 1953e1956.
[50] Md. J. Uddin, P.N. Praveen Rao, R. McDonald, E.E. Knaus, A new class of acyclic
2-alkyl-1,1,2-triaryl (Z)-olefins as selective cyclooxygenase-2 inhibitors,
J. Med. Chem. 47 (2004) 6108e6111.
[51] Hye-Jung Kim, Chong Hak Chae, Kyu Yang Yi, Kyung-Lae Park, Sung-eun Yoo,
Computational studies of COX-2 inhibitors: 3D-QSAR and docking, Bioorg.
Med. Chem. 12 (2004) 1629e1641.
[52] J.L. Wang, D. Limburg, M.J. Graneto, J. Springer, J.R.B. Hamper, S. Liao,
J.L. Pawlitz, R.G. Kurumbail, T. Maziasz, J.J. Talley, J.R. Kiefer, J. Carter, The
novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: the
second clinical candidate having a shorter and favorable human half-life,
Bioorg. Med. Chem. Lett. 20 (2010) 7159e7163.
[18] P.N. Rao, Q.H. Chen, E.E. Knaus, Synthesis and structure-activity relationship
studies of 1,3-diarylprop-2-yn-1-ones: dual inhibitors of cyclooxygenases and
lipoxygenases, J. Med. Chem. 49 (5) (2006) 1668e1683.
[19] M. Scholz, H.K. Ulbrich, G. Dannhardt, Investigations concerning the COX/5-
LOX inhibiting and hydroxyl radical scavenging potencies of novel 4,5-
diaryl isoselenazoles, Eur. J. Med. Chem. 43 (2008) 1152e1159.
[20] E. Pontiki, D. Hadjipavlou-Litina, K. Litinas, O. Nicolotti, A. Carotti, Design,
synthesis and pharmacobiological evaluation of novel acrylic acid deriva-
tives acting as lipoxygenase and cyclooxygenase-1 inhibitors with antioxi-
dant and anti-inflammatory activities, Eur. J. Med. Chem. 46 (2011)
191e200.
[21] Yue Li, Shu-Han Chen, Tian-Miao Ou, Jia-Heng Tan, Ding Li, Lian-Quan Gu, Zhi-
Shu Huang, Syntheses and characterization of nimesulide derivatives for dual
enzyme inhibitors of both cyclooxygenase-1/2 and 5-lipoxygenase, Bioorg.
Med.Chem. 19 (2011) 2074e2083.
[22] A.A. Geronikaki, A.A. Lagunin, D.I. Hadjipavlou-Litina, P.T. Elefteriou,
D.A. Filimonov, V.V. Poroikov, I. Alam, A.K. Saxena, Computer-aided discovery
of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase
inhibition, J. Med. Chem. 51 (2008) 1601e1609.
[23] M. Fischer, R.E. Hubbard, Fragment-based ligand discovery, Mol. Interven-
tions. 9 (2009) 23e30.
[53] R.G. Kurumbail, A.M. Stevens, J.K. Gierse, J.J. McDonald, R.A. Stegeman, J.Y. Pak,
D. Gildehaus, J.M. Miyashiro, T.D. Penning, K. Seibert, P.C. Isakson,
W.C. Stallings, Structural basis for selective inhibition of cyclooxygenase-2 by
anti-inflammatory agents, Nature 384 (1996) 644e648.
[54] S.W. Rowlinson, J.R. Kiefer, J.J. Prusakiewicz, J.L. Pawlitz, K.R. Kozak,
A.S. Kalgutkar, W.C. Stallings, R.G. Kurumbail, L.J. Marnett, A novel mechanism
[24] J.P. Overington, B. Al-Lazikani, A.L. Hopkins, How many drug targets are there?
Nat. Rev. Drug Discov. 5 (2006) 993e996.