Chemical Papers

, Volume 72, Issue 9, pp 2225–2237 | Cite as

Synthesis, molecular docking, and evaluation of novel bivalent pyrazolinyl-1,2,3-triazoles as potential VEGFR TK inhibitors and anti-cancer agents

  • Ahmed A. Abd-Rabou
  • Bakr F. Abdel-Wahab
  • Mohamed S. Bekheit
Original Paper


Investigations in the discovery of tyrosinase enzyme inhibitors have the potential to design novel anti-cancer drugs. A variety of novel bivalent pyrazolinyl triazoles 57 were synthesized and identified. The bis-acetyl triazole 3 was accomplished via two-step process first by preparation of diazide 2 followed its coupling reaction with acetylacetone in basic medium. The Claisen–Schmidt condensation reaction of 3 with two moles equivalent of benzaldehyde produces the corresponding bis-α, β-unsaturated ketone 4. Treatment of Schiff base 4 with excess hydrazine hydrate in either acetic acid or ethanol/DMF afforded the bis-N-acetylpyrazline 5 or bis-pyrazoline 6, respectively. Finally, treatment of 6 with two derivatives of isothiocyanate analog gives the bis-N-thioamide pyrazolines 7a and 7b. The synthesized compounds were evaluated as anti-tumor candidates against three human cancer cell lines (MCF-7, HepG2, and HCT-116). The bioscreening evaluation showed that compounds 7a and 6 had a significant antineoplastic potencies (IC50: 32.26 and 57.06 µg/mL) against breast MCF-7 and hepatic HepG2 cancerous cell lines, respectively, in relative to the standard drug, 5-fluorouracil. Molecular docking studies of the synthesized compounds were investigated as VEGFR2 TK inhibitors.

Graphical Abstract


Bivalent ligands Pyrazoline Triazole VEGFR2 Computer-assisted molecular model Anti-cancer activity 

Supplementary material

11696_2018_451_MOESM1_ESM.docx (21 kb)
Appendix 1: Elemental analysis results of new compounds (DOCX 20 kb)
11696_2018_451_MOESM2_ESM.xls (42 kb)
Appendix 2: Checklist for compound characterizations (XLS 41 kb)


  1. Abdou WM, Bekheit MS (2015) One pot three-component synthesis of peptidomimics for investigation of antibacterial and antineoplastic properties. Arab J Chem. Google Scholar
  2. Abd-Rabou AA (2017) Calcium, a cell cycle commander drives colon cancer cell diffpoptosis. Indian J Clin Biochem 32:9–18. CrossRefGoogle Scholar
  3. Abd-Rabou AA, Ahmed HH (2017) CS-PEG decorated PLGA nano-prototype for delivery of bioactive compounds: a novel approach for induction of apoptosis in HepG2 cell line. Adv Med Sci 62:357–367. CrossRefGoogle Scholar
  4. Abd-Rabou AA, Zoheir K, Ahmed HH (2012) Potential impact of curcumin and taurine on human hepatoma cells using Huh-7 cell line. Clin Biochem 45:1519–1521. CrossRefGoogle Scholar
  5. Abd-Rabou AA, Zoheir KMA, Kishta MS, Shalby AB, Ezzo MI (2016) Nano-micelle of moringa oleifera seed oil triggers mitochondrial cancer cell apoptosis. Asian Pac J Cancer Prev 17:4929–4933. Google Scholar
  6. Ahmed HH, Abd-Rabou AA, Hassan AZ, Kotob SE (2015) Phytochemical analysis and anti-cancer investigation of boswellia serrata bioactive constituents in vitro. Asian Pac J Cancer Prev 16:7179–7188. CrossRefGoogle Scholar
  7. Amin KM, Abou-Seri SM, Awadallah FM, Eissa AAM, Hassan GS, Abdulla MM (2015) Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells. Eur J Med Chem 90:221–231. CrossRefGoogle Scholar
  8. Baashen MA, Abdel-Wahab BF, El-Hiti GA (2016) Syntheses of triazoloquinoxalines. Heterocycles 92:1931–1952. CrossRefGoogle Scholar
  9. Bano S, Javed K, Ahmad S, Rathish IG, Singh S, Alam MS (2011) Synthesis and biological evaluation of some new 2-pyrazolines bearing benzene sulfonamide moiety as potential anti-inflammatory and anti-cancer agents. Eur J Med Chem 46:5763–5768. CrossRefGoogle Scholar
  10. Bekheit MS, Kamel AA (2017) Multi-Component reactions in preparation of α- and β- substituted phosphonates. Curr Org Chem 21:923–938. CrossRefGoogle Scholar
  11. Bekheit MS, Farahat AA, Abdel-Wahab BF (2016) Synthetic routes to thiazoloquinazoline. Chem Heterocycl Compd 52:766–772. CrossRefGoogle Scholar
  12. Berque-Bestel I, Lezoualc’h F, Jockers R (2008) Bivalent ligands as specific pharmacological tools for G protein-coupled receptor dimers. Curr Drug Discov Technol 5:312–318. CrossRefGoogle Scholar
  13. Bhuva HHA, Kini SG (2010) Synthesis, anticancer activity and docking of some substituted benzothiazoles as tyrosine kinase inhibitors. J Mol Graph Model 29:32–37. CrossRefGoogle Scholar
  14. Demchuk DV, Samet AV, Chernysheva NB, Ushkarov VI, Stashina GA, Konyushkin LD, Raihstat MM, Firgang SI (2014) Synthesis and antiproliferative activity of conformationally restricted 1,2,3-triazole analogues of combretastatins in the sea urchin embryo model and against human cancer cell line. Bioorg Med Chem 15:738–755. CrossRefGoogle Scholar
  15. George DJ (2007) Phase 2 studies of sunitinib and AG013736 in patients with cytokine-refractory renal cell carcinoma. Clin Cancer Res 13:753–757. CrossRefGoogle Scholar
  16. Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V (2014) SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res 42:W32–W38. CrossRefGoogle Scholar
  17. Gupta D, Jain DKJ (2015) Synthesis, antifungal and antibacterial activity of novel 1,2,4-triazole derivative. J Adv Pharm Technol Res 6:141–146. CrossRefGoogle Scholar
  18. Hassan AS, Hafez TS, Ali MM, Khatab TK (2016) Design, synthesis and cytotoxic activity of some new pyrazolines bearing benzofuran and pyrazole moieties. Res J Pharm Biol Chem Sci 7:417–429Google Scholar
  19. Hiller C, Kuhhorn J, Gmeiner PJ (2013) Class A G-Protein-Coupled receptor (GPCR) dimers and bivalent ligands. J Med Chem 56:6542–6559. CrossRefGoogle Scholar
  20. Kharb R, Yar MS, Sharma PC (2011) Recent advances and future perspectives of triazole analogs as promising antiviral agents. Mini Rev Med Chem 11:84–96. CrossRefGoogle Scholar
  21. Khaybullin RN, Zhang M, Fu J, Liang X, Li T, Katritzky AR, Okunieff P, Qi X (2014) Design and synthesis of isosteviol triazole conjugates for cancer therapy. Molecules 19:18676–18689. CrossRefGoogle Scholar
  22. Khazir J, Hyder I, Gayatri JL, Yandrati LP, Nalla N, Chasoo G, Mahajan A, Saxena AK, Alam MS, Qazi GN, Kumar HMS (2014) Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compound. Eur J Med Chem 82:255–262. CrossRefGoogle Scholar
  23. Lambert PA, Somers KD, Kohn EC, Perry RR (1997) Antiproliferative and antiinvasive effects of carboxyamido-triazole on breast cancer cell lines. Surgery 122:372–378CrossRefGoogle Scholar
  24. Li Z, Wan H, Shi Y, Ouyang P (2004) Personal experience with four kinds of chemical structure drawing software: review on ChemDraw, ChemWindow, ISIS/Draw, and ChemSketch. J Chem Inf Comput Sci 44:1886–1890. CrossRefGoogle Scholar
  25. Li D, Wang X, Jia Y, Wang A, Wu Y (2012) Synthesis of conjugated hyperbranched polytriazoles containing truxene units by click polymerization. Chin J Chem 30:861–868. CrossRefGoogle Scholar
  26. Lv P-C, Li D-D, Li Q-S, Lu X, Z-p Xiao, Zhu H-L (2011) Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives as EGFR TK inhibitors and potential anticancer agents. Bioorg Med Chem Lett 21:5374–5377. CrossRefGoogle Scholar
  27. Marella A, Ali R, Alam T, Saha R, Tanwar O, Akhter M, Shaquiquzzaman M, Alam MM (2013) Pyrazolines: a biological review. Mini Rev Med Chem 13:921–931. CrossRefGoogle Scholar
  28. Metwally MA, Abdel-Wahab BF, El-Hiti GA (2010) 2-Acetylbenzofurans: synthesis, reactions and application. Curr Org Chem 14:48–64. CrossRefGoogle Scholar
  29. Na JI, Na JY, Choi WY, Lee MC, Park MS, Choi KH, Lee JK, Kim KT, Park JT, Kim HS (2015) The HIF-1 inhibitor YC-1 decreases reactive astrocyte formation in a rodent ischemia model. Am J Transl Res 7:751–760Google Scholar
  30. Nussbaumer S, Bonnabry P, Veuthey J-L, Fleury-Souverain S (2011) Analysis of anticancer drugs: a review. Talanta 85:2265–2289. CrossRefGoogle Scholar
  31. Paprocka R, Wiese M, Eljaszewicz A, Helmin-Basa A, Gzella A, Modzelewska-Banachiewicz B, Michalkiewicz J (2015) Synthesis and anti-inflammatory activity of new 1,2,4-triazole derivative. Bioorg Med Chem Lett 25:2664–2667. CrossRefGoogle Scholar
  32. Parikh AA, Ellis LM (2004) The vascular endothelial growth factor family and its receptors. Hematol Oncol Clin North Am 18:951–971. CrossRefGoogle Scholar
  33. Pedretti A, Villa L, Vistoli g (2004) VEGA-An open platform to develop chemo-bio-informatics applications, using plug-in architecture and script programming. J Comput Aided Mol Des 18:167–173. CrossRefGoogle Scholar
  34. Pokhodylo N, Shyyka O, Matiychuk V (2013) Synthesis of 1,2,3-triazole derivatives and evaluation of their anticancer activity. Sci Pharm 81:663–676. CrossRefGoogle Scholar
  35. Powers DG, Casebier DS, Fokas D, Ryan WJ, Troth JR, Coffen DL (1998) Automated parallel synthesis of chalcone-based screening libraries. Tetrahedron 54:4085–4096. CrossRefGoogle Scholar
  36. Qin H-L, Shang Z-P, Jantan I, Tan OU, Hussain MA, Sher M, Bukhari SNA (2015a) Molecular docking studies and biological evaluation of chalcone based pyrazolines as tyrosinase inhibitors and potential anticancer agents. RSC Adv 5:46330–46338. CrossRefGoogle Scholar
  37. Qin Y-J, Li Y-J, Jiang A-Q, Yang M-R, Zhu Q-Z, Dong H, Zhu H-L (2015b) Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitor. Eur J Med Chem 94:447–457. CrossRefGoogle Scholar
  38. Rahman A, Siddiqui AA (2010) Pyrazoline derivatives: a worthy insight into the recent advances and potential pharmacological activities. Inter J Pharm Sci Drug Res 2:165–175Google Scholar
  39. Ramaswamy B, Mrozek E, Kuebler JP, Bekaii-Saab T, Kraut EH (2011) Phase II trial of pyrazoloacridine (NSC#366140) in patients with metastatic breast cancer. Investig New Drugs 29:347–351. CrossRefGoogle Scholar
  40. Ranieri G, Mammi M, di Paola ED, Russo E, Gallelli L, Citraro R, Gadaleta CD, Marech I, Ammendola M, de Sarro G (2014) Pazopanib a tyrosine kinase inhibitor with strong anti-angiogenetic activity: a new treatment for metastatic soft tissue sarcom. Crit Rev Oncol Hematol 89:322–329. CrossRefGoogle Scholar
  41. Rathore P, Yaseen S, Ovais S, Bashir R, Yaseen R, Hameed AD, Samim M, Gupta R, Hussain F, Javed K (2014) Synthesis and evaluation of some new pyrazoline substituted benzenesulfonylureas as potential antiproliferative agent. Bioorg Med Chem Lett 24:1685–1691. CrossRefGoogle Scholar
  42. Rebucci M, Michiels C (2013) Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 85:1219–1226. CrossRefGoogle Scholar
  43. Rosini M, Simoni E, Bartolini M, Soriano E, Marco-Contelles J, Andrisano V, Monti B, Windisch M, Hutter-Paier B, McClymont DW, Mellor LR, Bolognesi ML (2013) The bivalent ligand approach as a tool for improving the in vitro anti-alzheimer multitarget profile of dimebon. Chem Med Chem 8:1276–1281. CrossRefGoogle Scholar
  44. Shaaban MR, Mayhoub AS, Farag AM (2012) Recent advances in the therapeutic applications of pyrazoline. Expert Opin Ther Pat 22:253–291. CrossRefGoogle Scholar
  45. Shin SY, Yoon H, Hwang D, Ahn S, Kim D-W, Koh D, Lee YH, Lim Y (2013) Benzochalcones bearing pyrazoline moieties show anti-colorectal cancer activities and selective inhibitory effects on aurora kinases. Bioorg Med Chem 21:7018–7024. CrossRefGoogle Scholar
  46. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. Cancer J Clin 66:7–30. CrossRefGoogle Scholar
  47. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. Cancer J Clin 67:7–30. CrossRefGoogle Scholar
  48. Trott A, Olson J (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreadin. J Comput Chem 31:455–461. Google Scholar
  49. van Meerloo J, Kaspers GJ, Cloos J (2011) Cell sensitivity assays: the MTT assayCancer cell culture. Methods Mol Biol 731:237–245. CrossRefGoogle Scholar
  50. Varmus H (2006) The new era in cancer research. Science 312:1162–1165. CrossRefGoogle Scholar
  51. Vatmurge NS, Hazra BG, Pore VS, Shirazi F, Chavan PS, Mv Deshpande (2018) Synthesis and antimicrobial activity of β-lactam–bile acid conjugates linked via triazole. Bioorg Med Chem Lett 18:2043–2047. CrossRefGoogle Scholar
  52. Xu W, Pan Y, Wang H, Li H, Peng Q, Wei D, Chen C, Zheng J (2017) Synthesis and evaluation of new pyrazoline derivatives as potential anticancer agents in HepG2 cell line. Molecules 22:467–481. CrossRefGoogle Scholar
  53. Yusuf M, Jain P (2014) Synthetic and biological studies of pyrazolines and related heterocyclic compounds. Arab J Chem 7:553–596. CrossRefGoogle Scholar
  54. Zhu SL, Wu Y, Liu CJ, Wei CY, Tao JC, Liu HM (2013) Design and stereoselective synthesis of novel isosteviol-fused pyrazolines and pyrazoles as potential anticancer agents. Eur J Med Chem 65:70–82. CrossRefGoogle Scholar
  55. Zoheir KMA, Abd-Rabou AA, Harisa GI (2015) Gene expression of IQGAPs and Ras families in an experimental mouse model for hepatocellular carcinoma: a mechanistic study of cancer progression. Int J Clin Exp Pathol 8:8821–8831Google Scholar
  56. Zoheir KMA, Abd-Rabou AA, Harisa GI, Kumar A, Ahmad SF, Ansari MA, Abd-Allah AR (2016) IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma. Tumor Biol 37:13927–13939. CrossRefGoogle Scholar
  57. Zwick E, Bange J, Ullrich A (2001) Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 8:161–173. CrossRefGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Hormones Department, Medical Research DivisionNational Research CentreDokki, GizaEgypt
  2. 2.Applied Organic Chemistry DepartmentNational Research CentreDokki, GizaEgypt
  3. 3.Chemical Industries Research DivisionNational Research CentreDokki, CairoEgypt

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