Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Synthesis, anticancer evaluation, and molecular docking studies of benzoxazole linked combretastatin analogues


A novel series of benzoxazole linked combretastatin derivatives (11a11n) have been synthesized and confirmed by 1H NMR, 13C NMR, and Mass spectral analysis. The synthesized compounds (11a11n) were screened for anticancer activity against three human cancer cell lines, Breast (MCF-7), Lung (A549), and Melanoma (A375). Most of the compounds exhibit moderate to potent anticancer activity. Among the compounds, 11g, 11h, 11l, 11m, and 11n showed more potent activity than the positive control Doxorubicin. In addition, compounds 11g, 11l, 11m, and 11n were carried out their molecular docking studies on EGFR receptor (PDB ID: 4hjo) and results indicated that 11g and 11l have strong binding interactions with the receptor. It was found that the binding energy calculations were in good agreement with the observed IC50 values.

This is a preview of subscription content, log in to check access.

Fig. 1
Scheme 1
Fig. 2
Fig. 3


  1. Agarwal M, Singh V, Sharma SC, Sharma P, Ansari MdY, Jadav SS, Yasmin S, Sreenivasulu R, Hassan MdZ, Saini P, Ahsan MJ (2016) Design and synthesis of new 2,5-disubstituted-1,3,4-oxadiazole analogues as anticancer agents. Med Chem Res 25:2289–2303

  2. Ahsan MJ, Choudhary K, Jadav SS, Yasmin S, Ansari MY, Sreenivasulu R (2015) Synthesis, antiproliferative activity and molecular docking studies of curcumin, analogues bearing pyrazole ring. Med Chem Res 24:4166–4180

  3. American society for reproductive medicine (2013) Use of clomiphene citrate in infertile women: a committee opinion. Fertil Steril 100:341–348

  4. Clark DE, Eastwood PR, Harris NV, McCarthy C, Morley AD, Pickett SD (2000) Bicyclic compounds and their use as integrin receptor ligands. WO 2000049005A1

  5. Durgesh R, Sreenivasulu R, Raju RR (2018a) Synthesis and anti-tumor evaluation of Indole-substituted Indole fused keto hydrazide-hydrazones. J Pharm Res 12:42–46

  6. Durgesh R, Sreenivasulu R, Srinivasarao P, Raju RR (2018b) Synthesis and anti-tumor evaluation of novel 5-bromo indole-aryl ketohydrazide-hydrazone analogues. Asian J Chem 30:1201–1204

  7. Durgesh R, Sreenivasulu R, Srinivasarao P, Raju RR (2018c) Synthesis and anticancer evaluation of indazole-aryl hydrazide-hydrazone derivatives. J Ind Chem Soc 95:433–438

  8. Frisch MJ, Trucks GW, Schlegel HB (2009) Gaussian 09. Revision B.01 Gaussian, Inc., Wallingford CT

  9. Galbraith SM, Maxwel RJ, Lodge MA, Tozer GM, Wilson J, Taylor NJ, Stirling JJ, Sena L, Padhani AR, Rustin GS (2003) Combretastatin A-4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 15:2831–2842

  10. Hatti I, Sreenivasulu R, Jadav SS, Ahsan MJ, Raju RR (2015a) Synthesis and biological evaluat ion of 1,3,4-oxadiazole linked bis indole derivatives as anticancer agents. Monatsh Chem 146:1699–1705

  11. Hatti I, Sreenivasulu R, Jadav SS, Jayaprakash V, Kumar CG, Raju RR (2015b) Synthesis, cytotoxic activity and docking studies of new 4-aza podophyllotoxin derivatives. Med Chem Res 24:3305–3313

  12. Kumar D, Jacob MR, Reynolds MB, Kerwin SM (2002) Synthesis and evaluation of anticancer benzoxazoles and benzimidazoles related to UK-1. Bioorg Med Chem 10:3997–4004

  13. Laibekman AM, Jantzen HM, Conley PB, Fretto LJ, Scarborough RM (2003) Platelet ADP receptor inhibitors. US 6667306B1

  14. Li Q, Sham HL (2002) Discovery and development of antimitotic agents that inhibit tubulin polymerisation for the treatment of cancer. Expert Opin Ther Pat 12:1663–1702

  15. Lippert JW (2007) Vascular disrupting agents. Bioorg Med Chem 15:605–615

  16. Lin CM, Ho HH, Pettit GR, Hamel E (1989) Antimitotic natural products combretastatin A-4 and combretastatin A-2: studies on the mechanism of their inhibition of the binding of colchicine to tubulin. Biochemistry 28:6984–6991

  17. Madhavi S, Sreenivasulu R, Ansari MdY, Ahsan MJ, Raju RR (2016) Synthesis, biological evaluation and molecular docking studies of Pyridine incorporated chalcone derivatives as anticancer agents. Lett Org Chem 13:682–692

  18. Madhavi S, Sreenivasulu R, Jyotsna Y, Raju RR (2017a) Synthesis of chalcone incorporated quinazoline derivatives as anticancer agents. Saudi Pharm J 25:275–279

  19. Madhavi S, Sreenivasulu R, Raju RR (2017b) Synthesis and biological evaluation of oxadiazole incorporated ellipticine derivatives as anticancer agents. Monatsh Chem 148:933–938

  20. Monic R, Gregory JT, Konstantin HD, James RR (2013) Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat Rev 39:839–850

  21. Murty MSR, Ram KR, Rao RW, Yadav JS, Rao JV, Cheriyan VT, Anto RJ (2011) Synthesis and preliminary evaluation of 2-substituted-1,3-benzoxazole and 3-[(3-substituted)propyl]-1,3-benzoxazol-2(3H)-one derivatives as potent anticancer. Med Chem Res 20:576–586

  22. O’Donnell CJ, Rogers BN, Bronk BS, Bryce DK, Coe JW, Cook KK, Duplantier AJ, Evrard E, Hajos M, Hoffmann WE, Hurst RS, Aklad N, Mather RJ, McLean S, Nedza FM, ONeill BT, Peng L, Qian W, Rottas MM, Sands SB, Zhang L (2010) Discovery of 4-(5-Methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel α7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models. J Med Chem 53:1222–1237

  23. Oksuzoglu E, Tekiner-Gulbas B, Alper S, Temiz-Arpaci O, Ertan T, Yildiz I, Diril N, Sener-Aki E, Yalcin I (2008) Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors. J Enzym Inhib Med Chem 23:37–42

  24. Patterson DM, Rustin GJS (2007) Vascular damaging agents. Clin Oncol 19:443–456

  25. Pettit GR, Singh SB, Boyd MR, Hamel E, Pettit RK, Schmidt JM, Hogan F (1995) Antineoplastic agents. 291. isolation and synthesis of combretastatins A-4, A-5, and A-6. J Med Chem 38:1666–1672

  26. Pettit GR, Singh SB, Hamel E, Lin CM, Alberts DS, Garcia-Kendall D (1989) Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 45:209–211

  27. Pietro WJ, Francl MM, Hehre WJ, Defrees DJ, Pople JA, Binkley JSJ (1982) Self-consistent molecular orbital methods. 24. Supplemented small split-valence basis sets for second-row elements. J Am Chem Soc 104:5039–5084

  28. Raju RR, Chari AM, Ravindar K, Babu MCT, Rajendra W, Shobha D, Ravichandar M, Baburao K, Swamy LP (2016) Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of theophylline containing acetylenes and theophylline containing 1,2,3- triazoles with variant nucleoside derivatives. Eur J Med Chem 123:379–396

  29. Reddy NB, Burra VR, Ravindranath LK, Sreenivasulu R, Kumar VN (2016a) Synthesis and biological evaluation of benzoxazole fused combretastatin derivatives as anticancer agents. Monatsh Chem 147:593–598

  30. Reddy NB, Burra VR, Ravindranath LK, Kumar VN, Sreenivasulu R, Sadanandam P (2016b) Synthesis and biological evaluation of benzimidazole fused ellipticine derivatives as anticancer agents. Monatsh Chem 147:599–604

  31. Sato Y, Yamada M, Kobayashi K, Iwamatsu K, Konno F, Shudo K (1997) Benzaoxazole derivatives as serotonin 5-HT3 receptor partial activator. EP 806419 A1

  32. Schnurch M, Hammerle J, Stanetty P (2010) Product class 13: benzoxazoles and other annulated oxazoles, section 11.13. In: Science of Synthesis Updates

  33. Siemann DW, Chaplin DJ, Walicke PA (2009) A review and update of the current status of the vasculature-disabling agent combretastatin A-4 phosphate (CA4P). Expert Opin Investig Drugs 18:189–197

  34. Singh MS, Singh P, Singh S (2007) Synthesis of benzoxazole-2-ones, benzothiazole-2-ones and their 2-thione derivatives: Efficient conversion of 2-thione to 2-oxo derivatives. Indian J Chem 46:1666–1671

  35. Sreenivasulu R, Sujitha P, Jadav SS, Ahsan MJ, Kumar CG, Raju RR (2017) Synthesis, antitumor evaluation and molecular docking studies of Indole–Indazolyl hydrazide-hydrazone derivatives. Monatsh Chem 148:305–314

  36. Sreenivasulu R, Durgesh R, Jadav SS, Sujitha P, Kumar CG, Raju RR (2018) Synthesis, anticancer evaluation and molecular docking studies of bis(indolyl)triazinones, Nortopsentin analogs. Chem Pap 72:1369–1378

  37. Sreenivasulu R, Reddy KT, Jadav SS, Sujitha P, Kumar CG, Raju RR (2019) Synthesis, antiproliferative and apoptosis induction potential activities of novel bis(indolyl)hydrazide-hydrazone derivatives. Bioorg Med Chem.

  38. Subramanyam M, Sreenivasulu R, Rambabu G, Rao MVB, Rao KP (2018) Synthesis, biological evaluation and docking studies of 1,3,4-oxadiazole fused benzothiazole derivatives for anticancer drugs. Lett Drug Des Discov 15:2018

  39. Tamoxifen citrate-NCI (2015) Archived from the original on 4 January 2016. Retrieved 28 Nov 2015

  40. Ueki M, Ueno K, Miyadoh S, Abe K, Shibata K, Taniguchi M, Oi S (1993) UK-1, a novel cytotoxic metabolite from Streptomyces sp. 517-02. J Antibiot 46:1089–1094

Download references

Author information

Correspondence to K. R. S. Prasad.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kumar, V.K., Puli, V.S., Babu, A.V. et al. Synthesis, anticancer evaluation, and molecular docking studies of benzoxazole linked combretastatin analogues. Med Chem Res 29, 528–537 (2020).

Download citation


  • Combretastatin A-4
  • Benzoxazole
  • Anticancer activity
  • Docking