Synthesis and anti-inflammatory intestinal activity of new glucocorticoid derivatives

  • Marcella Gabrielle Mendes MachadoEmail author
  • Cauê Benito ScarimEmail author
  • Cleverton Roberto de Andrade
  • Jean Leandro dos Santos
  • Chung Man Chin
Original Research


Glucocorticoids (GCs) are used worldwide in the treatment of chronic inflammatory diseases. This study describes the synthesis of new glucocorticoid derivatives and evaluates anti-inflammatory activity in rat models with ulcerative colitis (UC). Six compounds (5a–f) were synthetized using the molecular hybridization strategy with yields of 40–80%. The compounds 5e and 5f showed a total regression of ulceration in 83.3% and 75% of treated animals, respectively. Moreover, 5e improved several clinical signs, such as weight gain and survival rates. The compounds 5a and 5c showed total regression of ulceration in 33.3% of the rats. This is higher than prednisolone. Glucocorticoid derivatives showed potential anti-inflammatory intestinal activity with regression of ulceration in colitis.


Molecular hybridization Phthalimide Colitis Prednisolone Budesonide 



The authors would like to thank the Brazilian Research Foundation FAPESP Process 2014/08728-6 for financial support.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The experiment and all the procedures were previously approved by the Research Ethics Committee of Animal Experimentation of the School of Pharmaceutical Sciences of Araraquara, São Paulo, Brazil (CEUA/FCFAr), under no. 11/2016. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Supplementary material

44_2019_2474_MOESM1_ESM.pdf (1 mb)
Supplementary Information


  1. Alanazi AM, El-Azab AS, Al-Suwaidan IA, ElTahir KEH, Asiri YA, Abdel-Aziz NI, Alaa AM (2015) Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: anti-inflammatory and analgesic activities. Eur J Med Chem 92:115–123CrossRefGoogle Scholar
  2. Ambrożak A, Steinebach C, Gardner ER, Beedie SL, Schnakenburg G, Figg WD, Gütschow M (2016) Synthesis and antiangiogenic properties of tetrafluorophthalimido and tetrafluorobenzamido barbituric acids. ChemMedChem 11:2621–2629CrossRefGoogle Scholar
  3. Ananthakrishnan AN, Xavier RJ, Podolsky DK (2017) Corticosteroids. In: Inflammatory bowel diseases: a clinician’s guide. John Wiley & Sons Ltd, Chichester, pp 75–83Google Scholar
  4. Awaad AS, El-Meligy RM, Soliman GA (2013) Natural products in treatment of ulcerative colitis and peptic ulcer. J Saudi Chem Soc 17:101–124CrossRefGoogle Scholar
  5. Bach DH, Liu JY, Kim WK, Hong JY, Park SH, Kim D, Qin SN, Luu TTT, Park HJ, Xu YN, Lee SK (2017) Synthesis and biological activity of new phthalimides as potential anti-inflammatory agents. Bioorg Med Chem 25:3396–3405CrossRefGoogle Scholar
  6. Barenholz Y, Gabizon AA, Avnir Y (2015) Liposomal compositions of glucocorticoid and glucocorticoid derivatives. US Patent 8932627Google Scholar
  7. Beedie SL, Rore HM, Barnett S, Chau CH, Luo W, Greig NH, Figg WD, Vargesson N (2016) In vivo screening and discovery of novel candidate thalidomide analogs in the zebrafish embryo and chicken embryo model systems. Oncotarget 7:33237–33245CrossRefGoogle Scholar
  8. Bhat MA, Al-omar MA, Ansari MA, Zoheir KM, Imam F, Attia SM, Bakheet SA, Nadeem A, Korashy HM, Voronkov A, Berishvili V, Ahmad SF (2015) Design and synthesis of n-arylphthalimides as inhibitors of glucocorticoid-induced TNF receptor-related protein, proinflammatory mediators, and cytokines in carrageenan-induced lung inflammation. J Med Chem 58:8850–8867CrossRefGoogle Scholar
  9. Billmeier U, Dieterich W, Neurath MF, Atreya R (2016) Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 22:9300–9313CrossRefGoogle Scholar
  10. Casal JJ, Bollini M, Lombardo ME, Bruno AM (2016) Thalidomide analogues: tumor necrosis factor-alpha inhibitors and their evaluation as anti-inflammatory agents. Eur J Pharm Sci 83:114–119CrossRefGoogle Scholar
  11. Christophi GP, Rengarajan A, Ciorba MA (2016) Rectal budesonide and mesalamine formulations in active ulcerative proctosigmoiditis: efficacy, tolerance, and treatment approach. Clin Exp Gastroenterol 9:125–130CrossRefGoogle Scholar
  12. Danese S, Colombel JF, Peyrin‐Biroulet L, Rutgeerts P, Reinisch W (2013) Review article: the role of anti‐TNF in the management of ulcerative colitis–past, present and future. Aliment Pharmacol Ther 37:855–866CrossRefGoogle Scholar
  13. Dinsen S, Baslund B, Klose M, Rasmussen AK, Friis-Hansen L, Hilsted L, Feldt-Rasmussen U (2013) Why glucocorticoid withdrawal may sometimes be as dangerous as the treatment itself. Eur J Intern Med 24:714–720CrossRefGoogle Scholar
  14. Fabia R, Willén R, Ar’rajab A, Andersson R, Ahrén B, Bengmark S (1992) Acetic acid-induced colitis in the rat: a reproducible experimental model for acute ulcerative colitis. Eur Surg Res 24:211–225CrossRefGoogle Scholar
  15. Fumery M, Dulai OS, Gupta S, Prokop LJ, Ramamoorthy S, Sandborn WJ, Singh S (2017) Incidence, risk factors, and outcomes of colorectal cancer in patients with ulcerative colitis with low-grade dysplasia: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 15:665–674CrossRefGoogle Scholar
  16. Harbord M, Eliakim R, Bettenworth D, Karmiris K, Katsanos K, Kopylov U, Kucharzik T, Molnár T, Raine T, Sebastian S, Sousa HT, Dignass A, Carbonnel F (2017) Third European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management. J Crohns Colitis 11:769–784CrossRefGoogle Scholar
  17. Marquez Ruiz JF, Kedziora K, Pigott M, Keogh B, Windle H, Gavin J, Kelleher DP, Gilmer JF (2013) A nitrophenyl-based prodrug type for colorectal targeting of prednisolone, budesonide and celecoxib. Bioorg Med Chem Lett 23:1693–1698CrossRefGoogle Scholar
  18. Mohamed SS, El-Hadi AA, Abo-Zied KM (2017) Biotransformation of prednisolone to hydroxy derivatives by Penicillium aurantiacum. Biocatal Biotransform 35:215–222CrossRefGoogle Scholar
  19. Naganuma M, Aoyama N, Suzuki Y, Nishino H, Kobayashi K, Hirai F, Watanabe K, Hibi T (2016) Twice-daily budesonide 2-mg foam induces complete mucosal healing in patients with distal ulcerative colitis. J Crohns Colitis 10:828–836CrossRefGoogle Scholar
  20. O’Donnell S, O’Morain CA (2010) Therapeutic benefits of budesonide in gastroenterology. Ther Adv Chronic Dis 1:177–186CrossRefGoogle Scholar
  21. Oray M, Abu Samra K, Ebrahimiadib N, Meese H, Foster CS (2016) Long-term side effects of glucocorticoids. Expert Opin Drug Saf 15:457–465CrossRefGoogle Scholar
  22. Pandit B, Hu Z, Chettiar SN, Zink J, Xiao Z, Etter JP, Bhasin D, Li PK (2013) Structure-activity relationship studies of thalidomide analogs with a taxol-like mode of action. Bioorg Med Chem Lett 23:6902–6904CrossRefGoogle Scholar
  23. Radin M, Sciascia S, Roccatello D, Cuadrado MJ (2017) Infliximab biosimilars in the treatment of inflammatory bowel diseases: a systematic review. BioDrugs 31:37–49CrossRefGoogle Scholar
  24. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW (2017) Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther 39:2216–2229CrossRefGoogle Scholar
  25. Rogler G (2014) Chronic ulcerative colitis and colorectal cancer. Cancer Lett 345:235–241CrossRefGoogle Scholar
  26. Santos JL, Chung MC (2013) Processo de obtenção de compostos derivados derivados de anti-inflamatórios esteróides (aies), composições farmacêuticas contendo tais compostos e seus usos no tratamento de doenças de caráter inflamatório. PI 110005943Google Scholar
  27. Seguro LPC, Rosario C, Shoenfeld Y (2013) Long-term complications of past glucocorticoid use. Autoimmun Rev 12:629–632CrossRefGoogle Scholar
  28. Sidoroff M, Kolho KL (2014) Screening for adrenal suppression in children with inflammatory bowel disease discontinuing glucocorticoid therapy. BMC Gastroenterol 14:51CrossRefGoogle Scholar
  29. Stidham RW, Lee TCH, Higgins PDR, Deshpande AR, Sussman DA, Singal AG, Elmunzer BJ, Saini SD, Vijan S, Waljee AK (2014) Systematic review with network meta‐analysis: the efficacy of anti‐tumour necrosis factor‐alpha agents for the treatment of ulcerative colitis. Aliment Pharmacol Ther 39:660–671CrossRefGoogle Scholar
  30. Strehl C, Buttgereit F (2013) Optimized glucocorticoid therapy: teaching old drugs new tricks. Mol Cell Endocrinol 380:32–40CrossRefGoogle Scholar
  31. Teixeira FV, Hosnec RS, Sobrado CW (2015) Management of ulcerative colitis: a clinical update. J Coloproctol 35:230–237CrossRefGoogle Scholar
  32. Thorlund K, Druyts E, Mills EJ, Fedorak RN, Marshall JK (2014) Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naive to anti-TNF therapy: an indirect treatment comparison meta-analysis. J Crohns Colitis 8:571–581CrossRefGoogle Scholar
  33. Tontini GE, Vecchi M, Pastorelli L, Neurath MF, Neumann H (2015) Differential diagnosis in inflammatory bowel disease colitis: state of the art and future perspectives. World J Gastroenterol 21:21–46CrossRefGoogle Scholar
  34. Ungar B, Levy I, Yavne Y, Yavzori M, Picard O, Fudim E, Loebstein R, Chowers Y, Eliakim R, Kopylov U, Ben-Horin S (2016) Optimizing anti-TNF-α therapy: serum levels of infliximab and adalimumab are associated with mucosal healing in patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol 14:550–557CrossRefGoogle Scholar
  35. Van Sandwijk MS, Bemelman FJ, Ten Berge IJ (2013) Immunosuppressive drugs after solid organ transplantation. Neth J Med 71:281–289PubMedGoogle Scholar
  36. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, Nallamothu BK (2017) Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 357:j1415CrossRefGoogle Scholar
  37. Yang Y, Li H, Sun H, Gong L, Guo L, Shi Y, Cai C, Gu H, Song Z, Yang L, Tong Y, Wei C, Zou Q, Zeng H (2016) A novel nitro-dexamethasone inhibits agr system activity and improves therapeutic effects in MRSA sepsis models without antibiotics. Sci Rep 6:20307CrossRefGoogle Scholar
  38. Zhou YH, Yu JP, Liu YF, Teng XJ, Ming M, Lv P, An P, Liu SQ, Yu HG (2006) Effects of Ginkgo biloba extract on inflammatory mediators (SOD, MDA, TNF-α, NF-κBp65, IL-6) in TNBS-induced colitis in rats. Mediators Inflamm 2006:1–9CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Pharmaceutical SciencesSão Paulo State University (UNESP)AraraquaraBrazil
  2. 2.School of DentistrySão Paulo State University (UNESP)AraraquaraBrazil

Personalised recommendations