Medicinal Chemistry Research

, Volume 27, Issue 2, pp 476–487 | Cite as

Exploring sulfonate esters of 5-arylidene thiazolidine-2,4-diones as PTP1B inhibitors with anti-hyperglycemic activity

  • Manoj Kumar Mahapatra
  • Rajnish Kumar
  • Manoj Kumar
Original Research


Protein tyrosine phosphatase 1B (PTP1B) has been identified as negative regulator of insulin and leptin signaling pathway, hence considered as a new therapeutic target of intervention for the treatment of type 2 diabetes. A series of eleven aryl/alkyl sulfonyloxy-5-arylidene thiazolidine-2,4-dione derivatives were synthesized and screened in vitro for PTP1B inhibitory activity and in vivo for anti-hyperglycemic activity. The introduction of aryl/alkyl sulfonate ester moiety was anticipated to yield PTP1B inhibitors with significant potency. Docking results revealed their bidentate nature of binding, and further helped in understanding the binding mode of ligands inside PTP1B enzyme. Compounds 13 and 14 were found to be potent PTP1B inhibitors with IC50 8.53 and 6.89 µM, respectively. Compounds 13, 14, and 18 have also shown significant lowering of blood glucose level as compared to pioglitazone.


PTP1B Diabetes Sulfonate ester 5-Arylidene-thiazolidine-2,4-dione Docking 



We gratefully acknowledge UGC (University Grant Commission), New Delhi, India for providing UGC-RFSMS fellowship to Manoj Kumar Mahapatra. We thank Mr. Avtar Singh (SAIF, Panjab University, Chandigarh, India) for doing the NMR study/characterization.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2074_MOESM1_ESM.docx (3.8 mb)
Supplementary data


  1. Bhattarai BR, Kafle B, Hwang JS, Khadka D, Lee SM, Kang JS, Ham SW, Han IO, Park H, Cho H (2009) Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects. Bioorg Med Chem Lett 19:6161–6165CrossRefPubMedGoogle Scholar
  2. Bhattarai BR, Kafle B, Hwang JS, Ham SW, Lee KH, Park H, Han IO, Cho H (2010) Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-γ activators. Bioorg Med Chem Lett 20:6758–6763CrossRefPubMedGoogle Scholar
  3. Byon JCH, Kusari AB, Kusari J (1998) Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem 182:101–108CrossRefPubMedGoogle Scholar
  4. Colagiuri S (2010) Diabesity: therapeutic options. Diabetes Obes Metab 12:463–473CrossRefPubMedGoogle Scholar
  5. Cooke DW, Plotnic L (2008) Type 1 diabetes mellitus in pediatrics. Pediatr Rev 29:374–384CrossRefPubMedGoogle Scholar
  6. Dhanachandra SK, Karthikeyan M, Kirubakaran P, Nagamani S (2011) Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors. J Mol Graph Model 30:186–197CrossRefGoogle Scholar
  7. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan CC, Ramachandran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–1548CrossRefPubMedGoogle Scholar
  8. Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shaw DE, Shelley M, Perry JK, Francis P, Shenkin PS (2004) Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem 47:1739–1749CrossRefPubMedGoogle Scholar
  9. Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein–ligand complexes. J Med Chem 49:6177–6196CrossRefPubMedGoogle Scholar
  10. Gum RJ, Gaede LL, Koterski S, Heindel M, Clampit JE, Zinker BA, Trevillyan JM, Ulrich R, Jirousek MR, Rondinone CM (2003) Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52:21–28CrossRefPubMedGoogle Scholar
  11. Huang P, Ramphal J, Wei J, Liang C, Jallal B, McMahon G, Tang C (2003) Structure-based design and discovery of novel inhibitors of protein tyrosine phosphatases. Bioorg Med Chem 11:1835–1849CrossRefPubMedGoogle Scholar
  12. Johnson TO, Ermolieff J, Jirousek MR (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1:696–709CrossRefPubMedGoogle Scholar
  13. Kaveeshwar SA, Cornwall J (2014) The current state of diabetes mellitus in India. Australas Med J 7:45–48CrossRefGoogle Scholar
  14. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479–5489CrossRefPubMedPubMedCentralGoogle Scholar
  15. Klopfenstein SR, Evdokimov AG, Colson AO, Fairweather NT, Neuman JJ, Maier MB, Gray JL, Gerwe GS, Stake GE, Howard BW, Farmer JA, Pokross ME, Downs TR, Kasibhatla B, Peters KG (2006) 1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors. Bioorg Med Chem Lett 16:1574–1578CrossRefPubMedGoogle Scholar
  16. Lagunin A, Stepanchikova A, Filimonov D, Poroikov V (2000) PASS: prediction of activity spectra for biologically active substances. Bioinformatics 16:747–748CrossRefPubMedGoogle Scholar
  17. Lakshminarayana N, Prasad YR, Gharat L, Thomas A, Narayanan S, Raghurama A, Srinivasan CV, Gopalan B (2010) Synthesis and evaluation of some novel dibenzo [b,d] furan carboxylic acids as potential anti-diabetic agents. Eur J Med Chem 45:3709–3718CrossRefPubMedGoogle Scholar
  18. Lepore SD, Mondal D (2007) Recent advances in heterolytic nucleofugal leaving groups. Tetrahedon 63:5103–5122CrossRefGoogle Scholar
  19. Li F, Wu X, Zou Y, Zhao T, Zhang M, Feng W, Yang L (2012) Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice. Food Chem Toxicol 50:1623–1631CrossRefPubMedGoogle Scholar
  20. Liu G (2004) Technology evaluation: ISIS-113715, Isis. Curr Opin Mol Ther 6:331–336PubMedGoogle Scholar
  21. Liu Z, Chai Q, Li YY, Shen Q, Ma LP, Zhang LN, Wang X, Sheng L, Li JY, Li J, Shen JK (2010) Discovery of novel PTP1B inhibitors with antihyperglycemic activity. Acta Pharmacol Sin 31:1005–1012CrossRefPubMedPubMedCentralGoogle Scholar
  22. Luo Y, Ma L, Zheng H, Chen L, Li R, He C, Yang S, Ye X, Chen Z, Li Z, Gao Y, Han J, He G, Yang L, Wei Y (2010) Discovery of (Z)-5-(4-Methoxybenzylidene)thiazolidine-2,4-dione, a readily available and orally active glitazone for the treatment of concanavalin a-induced acute liver injury of BALB/c mice. J Med Chem 53:273–281CrossRefPubMedGoogle Scholar
  23. Maccari R, Paoli P, Ottana R, Jacomelli M, Ciurleo R, Manao G, Steindl T, Langer T, Vigorita MG, Camici G (2007) 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. Bioorg Med Chem 15:5137–5149CrossRefPubMedGoogle Scholar
  24. Mahapatra MK, Kumar R, Kumar M (2017a) Bioorg Chem 71:1–9CrossRefPubMedGoogle Scholar
  25. Mahapatra MK, Kumar R, Kumar M (2017b) Med Chem Res 26:1176–1183CrossRefGoogle Scholar
  26. Martin B, Pallen CJ, Wang JH, Graves DJ (1985) Use of fluorinated tyrosine phosphates to probe the substrate specificity of the low molecular weight phosphatase activity of calcineurin. J Biol Chem 260:14932–14937PubMedGoogle Scholar
  27. Navarrete-Vázquez G, Torres-Gómez H, Hidalgo-Figueroa S, Ramírez-Espinosa JJ, Estrada-Soto S, Medina-Franco JL, León-Rivera I, Alarcón-Aguilar FJ, Almanza-Pérez JC (2014) Synthesis, in vitro and in silico studies of a PPARγ and GLUT-4 modulator with hypoglycemic effect. Bioorg Med Chem Lett 24:4575–4579CrossRefPubMedGoogle Scholar
  28. Peihong L, Yongli D, Lianhua S, Jingkang S, Qunyi L (2015) Novel, potent, selective and cellular active ABC type PTP1B inhibitors containing (methanesulfonyl-phenyl-amino)-acetic acid methyl ester phosphotyrosine mimetic. Bioorg Med Chem 23:7079–7088CrossRefGoogle Scholar
  29. Poroikov VV, Filimonov DA, Ihlenfeldt WD, Gloriozova TA, Lagunin AA, Borodina YV, Stepanchikova AV, Nicklaus MC (2003) PASS biological activity spectrum predictions in the enhanced open NCI database browser. J Chem Inf Comput Sci 43:228–236CrossRefPubMedGoogle Scholar
  30. PTP1B tyrosine phosphatase drug discovery kit manual: Available at QikProp, version 3. 5 (2012) Schrödinger, LLC, New York, NYGoogle Scholar
  31. Rondidone CM, Trevillyan JM, Clampit JE, Gum RJ, Berg C, Kroeger P, Frost L, Zinker BA, Reilly R, Ulrich R, Butler M, Monia BP, Jirousek MR, Waring JF (2002) Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. Diabetes 51:2405–2411CrossRefGoogle Scholar
  32. Sachan N, Kadam SS, Kulkarni VM (2007) Synthesis and antihyperglycemic activity and QSAR of 5-benzylidine-2,4-thiazolidinediones. Ind J Heterocycl Chem 17:57–62Google Scholar
  33. Walchi S, Curchod ML, Gobert RP, Arkinstall S, Huijsduijnen RH (2000) Identification of tyrosine phosphatases that dephosphorylate the insulin receptor. A brute force approach based on “substrate-trapping” mutants. J Biol Chem 275:9792–9796CrossRefGoogle Scholar
  34. Wang MY, Jin YY, Wei HY, Zhang LS, Sun SX, Chen XB, Dong WL, Xu WR, Cheng XC, Wang RL (2015) Synthesis, biological evaluation and 3D-QSAR studies of imidazolidine-2,4-dione derivatives as novel protein tyrosine phosphatase 1B inhibitors. Eur J Med Chem 103:91–104CrossRefPubMedGoogle Scholar
  35. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053CrossRefPubMedGoogle Scholar
  36. Xia Z, Knaak C, Ma J, Beharry MZ, McInnes BC, Wang W, Kraft AS, Smith CD (2009) Synthesis and evaluation of novel inhibitors of pim-1 and pim-2 protein kinases. J Med Chem 52:74–86CrossRefPubMedPubMedCentralGoogle Scholar
  37. Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, Wilcox D, Jacobson P, Frost L, Kroeger PE, Reilly RM, Koterski S, Opgenorth TJ, Ulrich RG, Crosby S, Butler M, Murray SF, McKay RA, Bhanot S, Monica BP, Jirousek MR (2002) PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA 99:11357–11362CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Manoj Kumar Mahapatra
    • 1
  • Rajnish Kumar
    • 1
  • Manoj Kumar
    • 1
  1. 1.University Institute of Pharmaceutical Sciences, Panjab UniversityChandigarhIndia

Personalised recommendations