In Silico Designing of Novel Thiazolidine-2-one Derivatives as Dual PDE4/7 Inhibitors for Inflammatory Disorders

Authors

  • Ajmer Singh Grewal Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab, India
  • Neelam Sharma Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
  • Sukhbir Singh Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
  • Sandeep Arora Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401

DOI:

https://doi.org/10.15415/jptrm.2017.52010

Keywords:

Anti-inflammatory activity, Docking, Drug design, Dual PDE4/7 inhibitors, Thiazolidine-2-one derivatives

Abstract

Phosphodiesterase 4 (PDE4) and phosphodiesterase 7 (PDE7), members of PDE super family, catalyse metabolism of secondary messenger cyclic adenosine monophosphate leading to augmented inflammatory processes in pro-inflammatory and immune-modulatory cells. Dual inhibitors of PDE4/7 are a novel class of drug candidates which can regulate pro-inflammatory as well as function of immune T-cell and are particularly beneficial for the treatment of various inflammatory diseases
devoid of unwanted actions. Intense efforts have been directed towards the development of effective dual inhibitors of both PDE4 and PDE7, but not much success has been reported till yet. The aim of present study was to design some newer substituted thiazolidine-2-one derivatives as dual inhibitors of PDE4/7 using structure based rational drug design approach. A new series of thiazolidine-2-one analogues were designed and molecular docking was performed using AutoDock Vina to explore the bonding
interactions of the designed molecules with the amino acid residues in the active site of target proteins. The docking study indicated that all the substituted thiazolidine-2-one derivatives have appreciable binding interactions with protein residues of both PDE4 and PDE7. The newly designed compounds could be used as lead molecules for development potent and non-toxic dual inhibitors of PDE4/7 for the management of various inflammatory conditions.

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References

Baumer, W., Hoppmann, J., Rundfeldt, C., & Kietzmann, M. (2007) Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflammation & Allergy - Drug Targets, 6, 17–26. https://doi.org/10.2174/187152807780077318

Beghè, B., Rabe, F., & Fabbri, L. M. (2013) Phosphodiesterase-4 inhibitor therapy for lung diseases. American Journal of Respiratory and Critical Care Medicine, 188, 271–278. https://doi.org/10.1164/rccm.201301-0021PP

Burnouf, C., & Pruniaux, M. P. (2002) Recent advances in PDE4 inhibitors as immune regulators and anti-inflammatory drugs. Current Pharmaceutical Design, 8, 1255–1296. https://doi.org/10.2174/1381612023394665

Caron, S., & Vazquez, E. (2001) The Synthesis of a Selective PDE4/TNFα Inhibitor. Organic Process Research&Development, 5, 587–592. https://doi.org/10.1021/op010223p

Castro, A., Jerez, M. J., Gil, C., & Martinez, A. (2005) Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors. Medicinal Research Reviews, 25(2), 229–244. https://doi.org/10.1002/med.20020

Christensen, I., Miskovicova, H., Porvaznik, I., Joskova, M., Mokra, D., & Mokry, J. (2012) Selective inhibition of phosphodiesterase 7 (PDE7) by BRL50481 in healthy and ovalbumin-sensitized guinea pigs. ActaMedicaMartiniana, 12, 16–23. https://doi.org/10.2478/v10201-011-0023-7

Conti, M., Richter, W., Mehats, C., Livera, G., Park, J., & Jin, C. (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. Journal of Biological Chemistry, 278, 5493–5496. https://doi.org/10.1074/jbc.R200029200

Felding, J., Soerensen, M. D., Poulsen, T. D., Larsen, J., Andersson, C., Refer, P., et al. (2014) 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. Journal of Medicinal Chemistry, 57, 5893–5903. https://doi.org/10.1021/jm500378a

Giembycz, M. A. (2002) Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Archives for Chest Disease, 57, 48–64.

Gil, C., Campillo, N. E., Perez, D. I., & Martinez, A. (2008) PDE7 inhibitors as new drugs for neurological and inflammatory disorders. Expert Opinion on Therapeutic Patents, 18, 1127–1139. https://doi.org/10.1517/13543776.18.10.1127

Gil, C., Casta-o, T., Campillo, M. N., Ballester, J. S., González, G. C., & Hernández, T. (2008a) Compound that is a dual inhibitor of enzymes PDE7 and/or PDE4, pharmaceutical compositions and uses applications. WO Patent 2008113881 A1.

Grewal, A. S., Lather, V., Pandita, D., & Dalal, R. (2017) Synthesis, docking and antiinflammatory activity of triazole amine derivatives as potential phosphodiesterase-4 inhibitors. Antiinflammatory and Antiallergy Agents in Medicinal Chemistry, 16(1), 58–67. https://doi.org/10.2174/1871523016666170616115752

Grewal, A. S., Kumar, P., Dua, J. S., & Lather, V. (2017a) Synthesis, docking and anti-inflammatory activity of some newer triazole derivatives as potential PDE7 inhibitors. Journal of Medicinal Chemistry & Toxicology, 2, 1-7.

Guariento, S., Karawajczyk, A., Bull, J. A., Marchini, G., Bielska, M., Iwanowa, X., et al. (2017) Design and synthesis of 4,5,6,7-tetrahydro-1H-1,2-diazepin7-one derivatives as a new series of phosphodiesterase 4 (PDE4) inhibitors. Bioorganic and Medicinal Chemistry Letters, 27, 24–29. https://doi.org/10.1016/j.bmcl.2016.11.040

Hatzelmann, A., Marx, D., Steinhilber, W., & Sterk, G. J. (2002) Phthalazinones derivatives useful as PDE4/7 inhibitors. WO Patent 2002085906 A3.

Jankowska, A., Świerczek, A., Chłoń-Rzepa, G., Pawłowski, M., & Wyska, E. (2017) PDE7-selective and dual inhibitors: advances in chemical and biological research. Current Medicinal Chemistry, 24, 673–700. https://doi.org/10.2174/0929867324666170116125159

Kodimuthali, A., Jabaris, S.S.L., & Pal, M. (2008) Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. Journal of Medicinal Chemistry, 18, 5471–5489. https://doi.org/10.1021/jm800582j

Lakics, V., Karran, E. H., & Boess, F. G. (2010) Quantitative comparison of phosphodiesterase mrna distribution in human brain and peripheral tissues. Neuropharmacology, 59(6), 367–374. https://doi.org/10.1016/j.neuropharm.2010.05.004

Levy, J., Zhou, D. M., & Zippin, J. H. (2016) Cyclic adenosine monophosphate signaling in inflammatory skin disease. Journal of Clinical & Experimental Dermatology Research, 7(1), 1000326.

Man, H.W., Schafer, P., Wong, L.M., Patterson, R.T., Corral, L.G., Raymon, H., et al. (2009) 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. Journal of Medicinal Chemistry, 52, 1522–1524. https://doi.org/10.1021/jm900210d

Miteva, M. A., Guyon, F., & Tufféry, P. (2010) Frog2: Efficient 3D conformation ensemble generator for small compounds. Nucleic Acids Research, 38, W622–627. https://doi.org/10.1093/nar/gkq325

Morris, G. M., Huey, R., Lindstrom, W., Sanner, M. F., Belew, R. K., Goodsell, D. S., et al. (2009) Autodock4 and AutoDockTools4: automated docking with selective receptor flexiblity. Journal of Computational Chemistry, 16, 2785–2791. https://doi.org/10.1002/jcc.21256

Nichols, P. J., Demattei, J. A., Barnett B. R., Lefur, N. A., Chuang, T. H., Piscopio, A. D., et al. (2006) Preparation of pyrrolidine-based PDE4 inhibitors via enantioselective conjugate addition of alpha-substituted malonates to aromatic nitroalkenes. Organic Letters, 8(7), 1495–1498. https://doi.org/10.1021/ol060398p

Pelcman, B., Yee, J. G., Mackenzie, L. F., Zhou, Y., & Han, K. (2010) Isochromenones useful in the treatment of inflammation. WO Patent 2010076564 A2.

Pitts, W. J., Watson, A. J., & Dodd, J. H. (2002) Dual inhibitors of PDE 7 and PDE 4. World Intellectual Property Organization 2002088079 A2.

Press, N. J., & Banner, K. H. (2009) PDE4 inhibitors - a review of the current field. Progress in Medicinal Chemistry, 47, 37–74. https://doi.org/10.1016/S0079-6468(08)00202-6

Redondo, M., Brea, J., Perez, D.I., Soteras, I., Val, C., Perez, C., et al. (2012) Effect of phosphodiesterase 7 (PDE7) inhibitors in experimental autoimmune encephalomyelitis mice. Discovery of a new chemically diverse family of compounds. Journal of Medicinal Chemistry, 55, 3274–3284. https://doi.org/10.1021/jm201720d

Rudra, S., Gupta, N., Chandrakant, K. G., Jain, T., Voleti, S. R., Ray, A., et al. (2012) Phosphodiestarase inhibitors. U.S. Patent 20120004201 A1.

Rudra, S., Gupta, N., Baregama, L. K., Agarwal, R., Khairnar, V. V., Ramaiah, M. R., et al. (2013) Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors. U.S. Patent 8420666 B2.

Sanz, M. J., Cortijo, J., & Morcillo, E. J. (2005) PDE4 inhibitors as new antiinflammatory drugs: Effects on cell trafficking and cell adhesion molecules expression. Pharmacology & Therapeutics, 106, 269–297. https://doi.org/10.1016/j.pharmthera.2004.12.001

Smith, S.J., Cieslinski, L.B., Newton, R., Donnelly, L.E., Fenwick, P.S., Nicholson, A.G., et al.(2004) 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. Molecular Pharmacology, 66, 1679–1689. https://doi.org/10.1124/mol.104.002246

Souness, J. E., Aldous, D., & Sargent, C. (2000) Immunosuppressive and antiinflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors. Immunopharmacology, 47, 127–162. https://doi.org/10.1016/S0162-3109(00)00185-5

Tasken, K., & Aandahl, E. M. (2004) Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiological Reviews, 84, 137–67. https://doi.org/10.1152/physrev.00021.2003

Trott, O., & Olson, A. J. (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multi threading. Journal of Computational Chemistry, 31, 455–461.

Vávrová, K. (2016) Emerging small-molecule compounds for treatment of atopic dermatitis: a review. Expert Opinion on Therapeutic Patents, 26(1), 21–34. https://doi.org/10.1517/13543776.2016.1101451

Vergne, F., Bernardelli, P., Lorthiois, E., Pham, N., Proust, E., Oliveira, C., et al. (2004) 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. Bioorganic Medicinal Chemistry Letters, 14, 4607–4613. https://doi.org/10.1016/j.bmcl.2004.07.009

Vergne, F., Bernardelli, P., Lorthiois, E., Pham, N., Proust, E., Oliveira, C., et al. (2004a) Discovery of thiadiazoles as a novel structural class of potent and selective PDE7 Inhibitors. part 2: Metabolism-directed optimization studies towards orally bioavailable derivatives. Bioorganic Medicinal Chemistry Letters, 14, 4615–4621. https://doi.org/10.1016/j.bmcl.2004.07.008

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Published

2019-05-28

How to Cite

Ajmer Singh Grewal, Neelam Sharma, Sukhbir Singh, & Sandeep Arora. (2019). In Silico Designing of Novel Thiazolidine-2-one Derivatives as Dual PDE4/7 Inhibitors for Inflammatory Disorders. Journal of Pharmaceutical Technology, Research and Management, 5(2), 149–162. https://doi.org/10.15415/jptrm.2017.52010

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