Synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of Ni(II) complexes with N,N,N′-trisubstituted thioureas

Abstract

A series of N,N,N′-trisubstituted thioureas (1–12) and their Ni(II) complexes (1a–12a) were synthesized and characterized by multinuclear (1H and 13C) NMR, FT-IR spectroscopy and LC–MS techniques in combination with elemental analysis. The crystal structures of both ligands and Ni(II) chelates of type Ni(L-O, S)2 were determined by single crystal X-ray diffraction analysis. All the complexes were adopted to have square planar geometry, where the N,N,N′-trisubstituted thioureas showed bidentate mode of coordination at nickel centre through oxygen and sulfur atoms. The synthesized complexes were screened for potential inhibitors of Jack bean urease. Compounds 1a and 3a were observed as most potent inhibitors of urease exhibiting IC50 values of 1.17 ± 0.12 and 1.19 ± 0.41 µM, respectively. Cytotoxicity assay on lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell showed that compounds were significant anticancer agents. Additionally, the complexes were tested against Leishmania major and found to be potent antileishmanial agents.

This is a preview of subscription content, access via your institution.

Scheme 1
Fig. 1
Fig. 2

Abbreviations

ETDA:

Ethylenediaminetetraacetic acid

MTT:

3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide

PBS:

Phosphate-buffered saline

SRB:

Sulforhodamine B

TCA:

Trichloroacetic acid

TLC:

Thin layer chromatography

References

  1. 1.

    Livingstone SE (1987) In: Gillard R D, McCleverty JA (eds) Comprehensive coordination chemistry. Pergamon, Oxford, p 639

    Google Scholar 

  2. 2.

    Janakiram-Sayala C, Bosman WP, Willemse J, Cras JA (1980) Recl Trav Chim Pays-Bas 99:314–316

    Article  CAS  Google Scholar 

  3. 3.

    Cheresova EN, Zhukova RS, Tatarintseva TB, Cheresov SV, Mukmeneva NA (1997) Russ J Gen Chem 67(8):1271–1275

    CAS  Google Scholar 

  4. 4.

    Beyer L, Criado JJ, Garcia E, Leβmann F, Medarde M, Richter R, Rodriguez E (1996) Tetrahedron 52:6233–6240

    Article  CAS  Google Scholar 

  5. 5.

    Bourne S, Koch KR (1993) J Chem Soc Dalton Trans 13:2071–2072

    Article  Google Scholar 

  6. 6.

    Aly AA, Ahmed EK, El-Mokadem KM, Hegazy MAF (2007) J Sulfur Chem 28:73–93

    Article  CAS  Google Scholar 

  7. 7.

    Aly AA, Nour-El-Din AM, Gomaa AM, Brown AB, Fahmi MS (2007) J Chem Res 439–441

  8. 8.

    Rauf MK, Talib A, Badshah A, Zaib S, Shoaib K, Shahid M, Flörke U, Imtiaz-ud-Din, Iqbal J (2013) Eur J Med Chem 70:487–496

  9. 9.

    Saeed A, Khan MS, Rafique H, Shahid M, Iqbal J (2014) Bioorg Chem 52:1–7

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Rauf MK, Imtiaz-ud-Din, Badshah A, Gielen M, Ebihara M, Vos D, Ahmed S (2009) J Inorg Biochem 103:1135–1144

  11. 11.

    Gul R, Rauf MK, Badshah A, Azam SS, Tahir MN, Khan A (2014) Eur J Med Chem 85:438–449

    Article  CAS  PubMed  Google Scholar 

  12. 12.

    Müller J, Limban C, Stadelmann B, Missir AV, Chirita IC, Chifiriuc MC, Nitulescu GM (2009) Parasitol Int 58:128–135

    Article  PubMed  Google Scholar 

  13. 13.

    Campo R, Criado JJ, Gheorghe R, Gonzalez FJ, Hermosa MR, Sanz F, Manzano JL, Monte E, Fernandez ER (2004) J Inorg Biochem 98:1307–1314

    Article  PubMed  Google Scholar 

  14. 14.

    Duan LP, Xue J, Xu LL, Zhang HB (2010) Molecules 15:6941–6947

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Zhong ZM, Xing R, Liu S, Wang L, Cai SB, Li PC (2008) Carbohydr Res 343:566–570

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Wang ZY, Wang S, Song XJ, Wang YG (2005) Chin J Pestic Sci 7:282–284

    CAS  Google Scholar 

  17. 17.

    Karplus PA, Pearson MA, Hausinger RP (1997) Acc Chem Res 30:330–337

    Article  CAS  Google Scholar 

  18. 18.

    Hausinger RP (ed) (1993) Biochemistry of nickel. Plenum Press, New York

    Google Scholar 

  19. 19.

    Mobley HLT, Hausinger RP (1989) Microbiol Rev 53:85–108

    PubMed Central  CAS  PubMed  Google Scholar 

  20. 20.

    Mobley HLT, Island MD, Hausinger RP (1995) Microbiol Rev 59:451–480

    PubMed Central  CAS  PubMed  Google Scholar 

  21. 21.

    Jabri E, Carr MB, Hausinger RP, Karplus PA (1995) Science 268:998–1004

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Krajewska B (2009) J Mol Catal B Enzym 59:9–21

    Article  CAS  Google Scholar 

  23. 23.

    Vassiliou S, Kosikowska P, Grabowiecka A, Yiotakis A, Kafarski P, Berlicki Ł (2010) J Med Chem 53:5597–5606

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Font M, Domínguez M-J, Sanmartín C, Palop JA, San-Francisco S, Urrutia O, Houdusse F, García-Mina JM (2008) J Agric Food Chem 56:8451–8460

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Domínguez M-J, Sanmartín C, Font M, Palop JA, San-Francisco S, Urrutia O, Houdusse F, García-Mina JM (2008) J Agric Food Chem 56:3721–3731

    Article  PubMed  Google Scholar 

  26. 26.

    Benini S, Rypniewski WR, Wilson KS, Ciurli S, Mangani S (2001) J Biol Inorg Chem 6:778–790

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Benini S, Rypniewski WR, Wilson KS, Mangani S, Ciurli S (2004) J Am Chem Soc 126:3714–3715

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Todd MJ, Hausinger RP (2000) Biochemistry 39:5389–5396

    Article  CAS  PubMed  Google Scholar 

  29. 29.

    Vassiliou S, Grabowiecka A, Kosikowska P, Yiotakis A, Kafarski P, Berlicki Ł (2008) J Med Chem 51:5736–5744

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Benini S, Rypniewski WR, Wilson KS, Ciurli S, Mangani S (1998) J Biol Inorg Chem 3:268–273

    Article  CAS  Google Scholar 

  31. 31.

    Todd MJ, Hausinger RP (1989) J Biol Chem 264:15835–15842

    CAS  PubMed  Google Scholar 

  32. 32.

    Hughes RB, Katz SA, Stubbins SE (1969) Enzymologia 36:332–334

    CAS  PubMed  Google Scholar 

  33. 33.

    Bruijnincx PCA, Sadler PJ (2008) Curr Opin Chem Biol 12:197–206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. 34.

    Storr T, Thompson KH, Orvig C (2006) Chem Soc Rev 35:534–544

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Hambley TW (2007) Dalton Trans pp. 4929–4937

  36. 36.

    Allardyce CS, Dyson PJ (2006) Top Organomet Chem 17:177–210

    CAS  Google Scholar 

  37. 37.

    Thompson KH, Orvig C (2006) Dalton Trans 761–764

  38. 38.

    Ronconi L, Sadler PJ (2007) Coord Chem Rev 251:1633–1648

    Article  CAS  Google Scholar 

  39. 39.

    Jakupec MA, Galanski M, Arion VB, Hartinger CG, Keppler BK (2008) Dalton Trans 183–194

  40. 40.

    Hanif M, Babak MV, Hartinger CG (2014) Drug Discov Today 19(10):1640–1648

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Dömötör O, Aicher S, Schmidlehner M, Novak MS, Roller A, Jakupec MA, Kandioller W, Hartinger CG, Keppler BK, Enyedy EA (2014) J Inorg Biochem 134:57–65

    Article  PubMed  Google Scholar 

  42. 42.

    Muhammad N, Guo Z (2014) Curr Opin Chem Biol 19:144–153

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Fricker SP, Mosi RM, Cameron BR, Baird I, Zhu Y, Anastassov V, Cox J, Doyle PS, Hansell E, Lau G, Langille J, Olsen M, Qin L, Skerlj R, Wong RSY, Santucci Z, McKerrow JH (2008) J Inorg Biochem 102:1839–1845

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Barbosa MIF, Corrêa RS, de Oliveira KM, Rodrigues C, Ellena J, Nascimento OR, Rocha VPC, Nonato FR, Macedo TS, Barbosa-Filho JM, Soares MBP, Batista AA (2014) J Inorg Biochem 136:33–39

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Gambino D (2011) Coord Chem Rev 255:2193–2203

    Article  CAS  Google Scholar 

  46. 46.

    Barnard PJ, Berners-Price SJ (2007) Coord Chem Rev 251:1889–1920

    Article  CAS  Google Scholar 

  47. 47.

    Hickey JL, Ruhayel RA, Barnard PJ, Baker MV, Berners-Price SJ, Filipovska A (2008) J Am Chem Soc 130:12570–12571

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Rigobello MP, Messori L, Marcon G, Bragadin M, Folda A, Scutari G, Bindoli A (2004) J Inorg Biochem 98:1634–1641

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Navarro M, Hernández C, Colmenares I, Hernández P, Fernández M, Sierraalta A, Marchán E (2007) J Inog Biochem 101:111–116

    Article  CAS  Google Scholar 

  50. 50.

    Singh MP, Mishra M, Khan A, Ramdas SL, Panjiyar S (1989) Br Med J 299:1318

    Article  CAS  Google Scholar 

  51. 51.

    Navarro M (2009) Coord Chem Rev 253:1619–1626

    Article  CAS  Google Scholar 

  52. 52.

    Rosenthal PJ (2004) Int J Parasitol 34:1489–1499

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Baiocco P, Colotti G, Franceschini S, Ilari A (2009) J Med Chem 52:2603–2612

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Sheldrick GM (2008) Acta Crystallogr A 64:112–122

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Weatherburn MW (1967) Anal Chem 39:971–974

    Article  CAS  Google Scholar 

  56. 56.

    Araki-Sasaki K, Aizawa S, Hiramoto M, Nakamura M, Iwase O, Nakata K, Sasaki Y, Mano T, Handa H, Tano Y (2000) J Cell Physiol 182:189–195

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) J Natl Cancer Inst 82:1107–1112

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Longo-Sorbello GS, Saydam G, Banerjee D, Bertino JR (2005) In: Celis JE, Carter N, Simons K, Small JV, Hunter T (eds) Cytotoxicity and cell growth assays. Cell biology, pp. 315–324

  59. 59.

    Mosmann T (1983) J Immunol Methods 65:55–63

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Niks M, Otto M (1990) J Immunol Methods 130:149–151

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The M. Khawar Rauf is thankful to the Quaid-e-Azam University, Islamabad, Pakistan, for the grant of funds for Post-doctoral Fellowship.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Amin Badshah or Jamshed Iqbal.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rauf, M.K., Yaseen, S., Badshah, A. et al. Synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of Ni(II) complexes with N,N,N′-trisubstituted thioureas. J Biol Inorg Chem 20, 541–554 (2015). https://doi.org/10.1007/s00775-015-1239-5

Download citation

Keywords

  • N,N,N′-trisubstituted thioureas
  • Nickel(II) complexes
  • Urease inhibition
  • Anticancer
  • Antileishmanial