Synthesis, Anti-inflammatory Activity and Docking Studies of Some Newer 1,3-Thiazolidine-2,4-dione Derivatives as Dual Inhibitors of PDE4 and PDE7

Author(s): Himanshu Sharma, Viney Lather*, Ajmer Singh Grewal, Deepti Pandita.

Journal Name: Current Computer-Aided Drug Design

Volume 15 , Issue 3 , 2019

Submit Manuscript
Submit Proposal

Graphical Abstract:


Abstract:

Background: Phosphodiesterase 4 (PDE4) and phosphodiesterase 7 (PDE7), PDE superfamily members, increase inflammatory processes in immunomodulatory as well as pro-inflammatory cells via breakdown of cyclic adenosine monophosphate. Dual inhibitors of PDE4 and PDE7 are a novel class of drug candidates which can regulate pro-inflammatory as well as T-cell function and can be particularly advantageous in the treatment of a wide-ranging disorders associated with the immune system as well as inflammatory diseases with fewer unwanted adverse effects.

Objective: The current research work was planned to design and synthesize some newer substituted 1,3- thiazolidine-2,4-dione derivatives as dual inhibitors of PDE4 and PDE7 followed by evaluation of their anti-inflammatory activity and in silico docking studies.

Methods: A new series of substituted 1,3-thiazolidine-2,4-dione derivatives was synthesized followed by evaluation of their anti-inflammatory activity in animal models. In silico docking studies were performed for the evaluation of the binding pattern of synthesized derivatives in the binding site of both PDE4 and PDE7 proteins.

Results: Amongst the newly synthesized derivatives, compounds 5 and 12 showed higher antiinflammatory activity in the animal model. The results of in vivo animal studies were found to be in concordance with the results of molecular docking studies.

Conclusion: These newly synthesized derivatives can act as the lead molecules for the design of safe and therapeutically effective agents for various inflammatory diseases acting via inhibition of both PDE4 and PDE7.

Keywords: Anti-inflammatory activity, cAMP, dual PDE4 and PDE7 inhibitors, inflammation, thiazolidinedione derivatives, docking studies.

[1]
Conti, M.; Richter, W.; Mehats, C.; Livera, G.; Park, J.; Jin, C. Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J. Biol. Chem., 2003, 278, 5493-5496.
[2]
Baumer, W.; Hoppmann, J.; Rundfeldt, C.; Kietzmann, M. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm. Allergy Drug Targets, 2007, 6, 17-26.
[3]
Souness, J.E.; Aldous, D.; Sargent, C. Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology, 2000, 47, 127-162.
[4]
Castro, A.; Jerez, M.J.; Gil, C.; Martinez, A. Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors. Med. Res. Rev., 2005, 25, 229-244.
[5]
Tasken, K.; Aandahl, E.M. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol. Rev., 2004, 84, 137-167.
[6]
Giembycz, M.A. Development status of second generation PDE4 inhibitors for asthma and COPD: The story so far. Monaldi Arch. Chest Dis., 2002, 57, 48-64.
[7]
Caron, S.; Vazquez, E. The synthesis of a selective PDE4/TNFα inhibitor. Org. Process Res. Dev., 2001, 5, 587-592.
[8]
Felding, J.; Soerensen, M.D.; Poulsen, T.D.; Larsen, J.; Andersson, C.; Refer, P.; Engell, K.; Ladefoged, L.G.; Thormann, T.; Vinggaard, A.M.; Hegardt, P.; Soehoel, A.; Nielsen, S.F. Discovery and early clinical development of 2-6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J. Med. Chem., 2014, 57, 5893-5903.
[9]
Press, N.J.; Banner, K.H. PDE4 inhibitors - A review of the current field. Prog. Med. Chem., 2009, 47, 37-74.
[10]
Burnouf, C.; Pruniaux, M.P. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr. Pharm. Des., 2002, 8, 1255-1296.
[11]
Sanz, M.J.; Cortijo, J.; Morcillo, E.J. PDE4 inhibitors as new anti-inflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression. Pharmacol. Ther., 2005, 106, 269-297.
[12]
Kodimuthali, A.; Jabaris, S.S.L.; Pal, M. Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. J. Med. Chem., 2008, 18, 5471-5489.
[13]
Beghè, B.; Rabe, F.; Fabbri, L.M. Phosphodiesterase-4 inhibitor therapy for lung diseases. Am. J. Respir. Crit. Care Med., 2013, 188, 271-278.
[14]
Man, H.W.; Schafer, P.; Wong, L.M.; Patterson, R.T.; Corral, L.G.; Raymon, H.; Blease, K.; Leisten, J.; Shirley, M.A.; Tang, Y.; Babusis, D.M.; Chen, R.; Stirling, D.; Muller, G.W. Discovery of (S)-N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl] acetamide (apremilast), a potent and orally active phosphodiesterase 4 and tumor necrosis factor-alpha inhibitor. J. Med. Chem., 2009, 52, 1522-1524.
[15]
Guariento, S.; Karawajczyk, A.; Bull, J.A.; Marchini, G.; Bielska, M.; Iwanowa, X.; Bruno, O.; Fossa, P.; Giordanetto, F. Design and synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin-7-one derivatives as a new series of phosphodiesterase 4 (PDE4) inhibitors. Bioorg. Med. Chem. Lett., 2017, 27, 24-29.
[16]
Grewal, A.S.; Lather, V.; Pandita, D.; Dalal, R. Synthesis, docking and anti-inflammatory activity of triazole amine derivatives as potential phosphodiesterase-4 inhibitors. Antiinflamm. Antiallergy Agents Med. Chem., 2017, 16(1), 58-67.
[17]
Grewal, A.S.; Kumar, P.; Dua, J.S.; Lather, V. Synthesis, docking and anti-inflammatory activity of some newer triazole derivatives as potential PDE7 inhibitors. J. Med. Chem. Toxicol., 2017, 2(2), 55-61.
[18]
Gil, C.; Campillo, N.E.; Perez, D.I.; Martinez, A. PDE7 inhibitors as new drugs for neurological and inflammatory disorders. Expert Opin. Ther. Pat., 2008, 18, 1127-1139.
[19]
Redondo, M.; Brea, J.; Perez, D.I.; Soteras, I.; Val, C.; Perez, C.; Morales-García, J.A.; Alonso-Gil, S.; Paul-Fernandez, N.; Martin-Alvarez, R.; Cadavid, M.I.; Loza, M.I.; Perez-Castillo, A.; Mengod, G.; Campillo, N.E.; Martinez, A.; Gil, C. Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds. J. Med. Chem., 2012, 55, 3274-3284.
[20]
Smith, S.J.; Cieslinski, L.B.; Newton, R.; Donnelly, L.E.; Fenwick, P.S.; Nicholson, A.G.; Barnes, P.J.; Barnette, M.S.; Giembycz, M.A. Discovery of BRL 50481 [3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene], a selective inhibitor of phosphodiesterase 7: In vitro studies in human monocytes, lung macrophages, and CD8+ T-lymphocytes. Mol. Pharmacol., 2004, 66, 1679-1689.
[21]
Christensen, I.; Miskovicova, H.; Porvaznik, I.; Joskova, M.; Mokra, D.; Mokry, J. Selective inhibition of phosphodiesterase 7 (PDE7) by BRL50481 in healthy and ovalbumin-sensitized guinea pigs. Acta Medica Martiniana, 2012, 12, 16-23.
[22]
Lakics, V.; Karran, E.H.; Boess, F.G. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology, 2010, 59, 367-374.
[23]
Pitts, W.J.; Watson, A.J.; Dodd, J.H. Dual inhibitors of PDE 7 and PDE 4. W.O. Patent 2002088079, Jan 30, 2002.
[24]
Rudra, S.; Gupta, N.; Chandrakant, K.G.; Jain, T.; Voleti, S.R.; Ray, A.; Dastidar, S.G.; Vijaykrishnan, L. Phosphodiestarase inhibitors. U.S. Patent 20120004201, Jan 05, 2012.
[25]
Rudra, S.; Gupta, N.; Baregama, L.K.; Agarwal, R.; Khairnar, V.V.; Ramaiah, M.R.; Palle, V.P.; Balachandran, S.; Kondaskar, A.; Salla, M.; Ray, A.; Dastidar, S.G.; Vijaykrishnan, L. Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors. U.S. Patent 8420666, Nov 18, 2013.
[26]
Vávrová, K. Emerging small-molecule compounds for treatment of atopic dermatitis: A review. Expert Opin. Ther. Pat., 2016, 26(1), 21-34.
[27]
Levy, J.; Zhou, D.M.; Zippin, J.H. Cyclic adenosine monophosphate signaling in inflammatory skin disease. J. Clin. Exp. Dermatol. Res., 2016, 7(1), 1000326.
[28]
Hatzelmann, A.; Marx, D.; Steinhilber, W.; Sterk, G.J. Phthalazinones derivatives useful as PDE4/7 inhibitors. W.O. Patent 2002085906, Dec 19, 2002.
[29]
Pelcman, B.; Yee, J.G.; Mackenzie, L.F.; Zhou, Y.; Han, K. Isochromenones useful in the treatment of inflammation. W.O. Patent 2010076564, July 08, 2010.
[30]
Jankowska, A.; Świerczek, A.; Chłoń-Rzepa, G.; Pawłowski, M.; Wyska, E. PDE7-selective and dual inhibitors: Advances in chemical and biological research. Curr. Med. Chem., 2017, 24, 673-700.
[31]
Nichols, P.J.; Demattei, J.A.; Barnett, B.R.; Lefur, N.A.; Chuang, T.H.; Piscopio, A.D.; Koch, K. Preparation of pyrrolidine-based PDE4 inhibitors via enantioselective conjugate addition of alpha-substituted malonates to aromatic nitroalkenes. Org. Lett., 2006, 8, 1495-1498.
[32]
Vergne, F.; Bernardelli, P.; Lorthiois, E.; Pham, N.; Proust, E.; Oliveira, C.; Mafroud, A.K.; Royer, F.; Wrigglesworth, R.; Schellhaas, J.; Barvian, M.; Moreau, F.; Idrissi, M.; Tertre, A.; Bertin, B.; Coupe, M.; Berna, P.; Soulard, P. Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 inhibitors. Part 1: Design, synthesis and structure-activity relationship studies soulard, P. Bioorg. Med. Chem. Lett., 2004, 14, 4607-4613.
[33]
Vergne, F.; Bernardelli, P.; Lorthiois, E.; Pham, N.; Proust, E.; Oliveira, C.; Mafroud, A.K.; Ducrot, P.; Wrigglesworth, R.; Berlioz-Seux, F.; Coleon, F.; Chevalier, E.; Moreau, F.; Idrissi, M.; Tertre, A.; Descours, A.; Berna, P.; Li, M. Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 Inhibitors. Part 2: Metabolism-directed optimization studies towards orally bioavailable derivatives. Bioorg. Med. Chem. Lett., 2004, 14, 4615-4621.
[34]
Tiwari, D.; Haque, S.; Mishra, S.; Chandra, R. Synthesis and pharmacological screening of N-substituted anthranilic acid derivatives. Int. J. Drug Develop. Res., 2011, 3(2), 265-271.
[35]
Mane, B.Y.; Vidyadhara, S. Synthesis and screening of anti-inflammatory activity of benzofuran derivatives bearing oxadiazole. Orient. J. Chem., 2011, 27(3), 1227-1231.
[36]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J. Comput. Chem., 2010, 31, 455-461.
[37]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 16, 2785-2791.
[38]
MarvinSketch 15.9.21.0, ChemAxon. Ltd. Budapest, Hungary. (https://chemaxon.com/products/marvin)
[39]
Miteva, M.A.; Guyon, F.; Tufféry, P. Frog2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Res., 2010, 38, W622-627.
[40]
The PyMOL Molecular Graphics System, Version 1.7.4.5 Edu, Schrödinger, LLC.
[41]
Grewal, A.S.; Lather, V.; Pandita, D.; Bhayana, G. Synthesis, docking and evaluation of phenylacetic acid and trifluoro-methylphenyl substituted benzamide derivatives as potential PPARδ agonists. Lett. Drug Des. Discov., 2017, 11, 1239-1251.
[42]
Singh, R.; Lather, V.; Pandita, D.; Judge, V.; Arumugam, K.N.; Grewal, A.S. Synthesis, docking and antidiabetic activity of some newer benzamide derivatives as potential glucokinase activators. Lett. Drug Des. Discov., 2017, 14, 540-553.
[43]
Lather, V.; Grewal, A.S.; Sharma, S.K.; Pandita, D. Synthesis, docking and evaluation of novel pyrazole carboxamide derivatives as multifunctional anti-Alzheimer’s agents. J. Med. Chem. Toxicol., 2017, 2, 47-54.


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [225 - 234]
Pages: 10
DOI: 10.2174/1573409914666181003151528
Price: $58

Article Metrics

PDF: 25
HTML: 3