Medicinal Chemistry Research

, Volume 27, Issue 2, pp 560–570 | Cite as

Design, synthesis and cytotoxicity evaluation of pyrazolyl pyrazoline and pyrazolyl aminopyrimidine derivatives as potential anticancer agents

  • Raquib Alam
  • Aftab Alam
  • Amulya K. Panda
  • RahisuddinEmail author
Original Research


In an attempt to find bio-active heterocyclic analogues, a series of novel 1-(5-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazol-1-yl)ethanones 5a–i and 4-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-6-(pyridine-3-yl)pyrimidin-2-amines 6a–i were designed, synthesized, and evaluated for their in vitro cytotoxicity against a panel of human cancer cell lines namely, HeLa (human cervix), NCI-H460 (human lung), PC-3 (human prostate), and NIH-3T3 (mouse embryo fibroblasts) cell lines. Most of these compounds exhibited moderate to good cytotoxicity against the tested cancer cell lines and weak toxicity against normal cell line. Analogs 5f, 5g, 5i, 6b–g showed significant cytotoxicity as compared to the standard drug etoposide. The compound 6g exhibited superior activity with IC50 value of 5.47 ± 0.44 µM against Hela cancer cell line.


Pyrazolylpyrazolines Pyrazolyl aminopyrimidines Michael addition Cytotoxicity MTT assay 



The authors thank to the Head, Department of Chemistry, Jamia Millia Islamia, New Delhi for providing research facilities. AIRF, JNU is acknowledged for 13C NMR spectra. Raquib Alam is also thankful to UGC, New Delhi for BSR fellowship.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2082_MOESM1_ESM.docx (6.6 mb)
Supplementary Information


  1. Abdel-Halim M, Diesel B, Kiemer AK, Abadi AH, Hartmann RW, Engel M (2014) Discovery and optimization of 1,3,5-trisubstituted pyrazolines as potent and highly selective allosteric inhibitors of protein kinase C-ζ. J Med Chem 57:6513–6530CrossRefPubMedGoogle Scholar
  2. Acker TM, Khatri A, Vance KM, Slabber C, Bacsa J, Snyder JP, Traynelis SF, Liotta DC (2013) Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists. J Med Chem 56:6434–6456CrossRefPubMedPubMedCentralGoogle Scholar
  3. Alam R, Alam MA, Panda AK, Rahisuddin (2016a) Design, synthesis and cytotoxicity evaluation of novel (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-(pyridin-3-yl)prop-2-en-1-ones as anticancer agents. Heterocycl Commun 22:221–225CrossRefGoogle Scholar
  4. Alam R, Alam MA, Panda AK, Rahisuddin (2017) Design, synthesis and cytotoxicity evaluation of 3-(5-(3-(aryl)-1-phenyl-1H-pyrazol-4-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)pyridine and 5-(3-(aryl)-1-phenyl-1h-pyrazol-4-yl)-3-(pyridin-3-yl)-4,5-dihydropyrazole-1-carbaldehyde derivatives as potential anticancer agents. J Heterocycl Chem 54:1812–1821CrossRefGoogle Scholar
  5. Alam R, Wahi D, Singh R, Sinha D, Tandon V, Grover A, Rahisuddin (2016b) Design, synthesis, cytotoxicity, human topoisomerase iiα inhibitory activity and molecular docking studies of pyrazole derivatives as potential anticancer agents. Bioorg Chem 69:77–90CrossRefPubMedGoogle Scholar
  6. Altıntop MD, Özdemir A, Turan-Zitouni G, Ilgın S, Atl Ö, Demirel R, Kaplancıklı ZA (2015) A novel series of thiazolyl-pyrazoline derivatives: synthesis and evaluation of antifungal activity, cytotoxicity and genotoxicity. Eur J Med Chem 92:342–352CrossRefPubMedGoogle 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 90:221–231CrossRefPubMedGoogle Scholar
  8. Badavath VN, Baysal I, Ucar G, Sinha BN, Jayaprakash V (2016) Monoamine oxidase inhibitory activity of novel pyrazoline analogues: curcumin based design and synthesis. ACS Med Chem Lett 7:56–61CrossRefPubMedGoogle Scholar
  9. Bronson J, Dhar M, Ewing W, Lonberg N (2012) Chapter thirty-one -to market, to market-2011. Annu Rep Med Chem 47:499–569CrossRefGoogle Scholar
  10. Casimiro-Garcia A, Piotrowski DW, Ambler C, Arhancet GB, Banker ME, Banks T, Boustany-Kari CM, Cai C, Chen X, Eudy R, Hepworth D, Hulford CA, Jennings SM, Loria PM, Meyers MJ, Petersen DN, Raheja NK, Sammons M, She L, Song K, Vrieze D, Wei L (2014) Identification of (R)-6-(1-(4-cyano-3-methylphenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl)-2-methoxynicotinic acid, a highly potent and selective nonsteroidal mineralocorticoid receptor antagonist. J Med Chem 57:4273–4288CrossRefPubMedGoogle Scholar
  11. Chen W, Ge X, Xu F, Zhang Y, Liu Z, Pan J, Song J, Dai Y, Zhou J, Feng J, Liang G (2015) Design, synthesis and biological evaluation of paralleled Aza resveratrol-chalcone compounds as potential anti-inflammatory agents for the treatment of acute lung injury. Bioorg Med Chem Lett 25:2998–3004CrossRefPubMedGoogle Scholar
  12. Desai NC, Joshi VV, Rajpara KM, Vaghani HV, Satodiya HM (2012) Facile synthesis of novel fluorine containing pyrazole based thiazole derivatives and evaluation of antimicrobial activity. J Fluorine Chem 142:67–78CrossRefGoogle Scholar
  13. Elkady M, Nieß R, Schaible AM, Bauer J, Luderer S, Ambrosi G, Werz O, Laufer SA (2012) Modified acidic nonsteroidal anti-inflammatory drugs as dual inhibitors of mPGES-1 and 5-LOX. J Med Chem 55:8958–8962CrossRefPubMedGoogle Scholar
  14. Giridhar R, Tamboli RS, Ramajayam R, Prajapati DG, Yadav MR (2012) Assessment of antiplatelet activity of 2-aminopyrimidines. Eur J Med Chem 50:428–432CrossRefPubMedGoogle Scholar
  15. Insuasty B, Tigreros A, Orozco F, Quiroga J, Abonia R, Nogueras M, Sanchez A, Cobo J (2010) Synthesis of novel pyrazolic analogues of chalcones and their 3-aryl-4-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)-1-phenyl-1H-pyrazole derivatives as potential antitumor agents. Bioorg Med Chem 18:4965–4974CrossRefPubMedGoogle Scholar
  16. Karad SC, Purohit VB, Raval DK (2014) Design, synthesis and characterization of fluoro substituted novel pyrazolylpyrazolines scaffold and their pharmacological screening. Eur J Med Chem 84:51–58CrossRefPubMedGoogle Scholar
  17. Kharbanda C, Alam MS, Hamid H, Javed K, Bano S, Dhulap A, Ali Y, Nazreen S, Haider S (2014) Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents. Bioorg Med Chem 22:5804–5812CrossRefPubMedGoogle Scholar
  18. Kharbanda C, Alam MS, Hamid H, Javed K, Dhulap A, Bano S, Ali Y (2015) Antidiabetic effect of novel benzenesulfonylureas as PPAR-γ agonists and their anticancer effect. Bioorg Med Chem Lett 25:4601–4605CrossRefPubMedGoogle Scholar
  19. Khunt RC, Khedkar VM, Chawda RS, Chauhan NA, Parikh AR, Coutinho EC (2012) Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4- fluorophenyl)-4-substituted pyrazole derivatives. Bioorg Med Chem Lett 22:666–678CrossRefPubMedGoogle Scholar
  20. Küçükgüzel SG, Senkardes S (2015) Recent advances in bioactive pyrazoles. Eur J Med Chem 97:786–815CrossRefPubMedGoogle Scholar
  21. Kulp SK, Yang YT, Hung CC, Chen KF, Lai JP, Tseng PH, Fowble JW, Ward PJ, Chen CS (2004) 3-Phosphoinositide-dependent protein kinase-1/Akt signaling represents a major cyclooxygenase-2-independent target for celecoxib in prostate cancer cells. Cancer Res 64:1444–1451CrossRefPubMedGoogle Scholar
  22. Lee J, Kim K-H, Jeong S (2011) Discovery of a novel class of 2-aminopyrimidines as CDK1 and CDK2 inhibitors. Bioorg Med Chem Lett 21:4203–4205CrossRefPubMedGoogle Scholar
  23. Meyers MJ, Arhancet GB, Hockerman SL, Chen X, Long SA, Mahoney MW, Rico JR, Garland DJ, Blinn JR, Collins JT, Yang S, Huang HC, McGee KF, Wendling JM, Dietz JD, Payne MA, Homer BL, Heron MI, Reitz DB, Hu X (2010) Discovery of (3S,3aR)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (PF-3882845), an orally efficacious mineralocorticoid receptor (MR) antagonist for hypertension and nephropathy. J Med Chem 53:5979–6002CrossRefPubMedGoogle Scholar
  24. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  25. Powers DG, Casebier DS, Fokas D, Ryan WJ, Troth JR, Coffen DL (1998) Automated parallel synthesis of chalcone based screening libraries. Tetrahedron 54:4085–4096CrossRefGoogle Scholar
  26. Prakash O, Pannu K, Kumar A (2006) Synthesis of some new 2-(3-aryl-1-phenyl-4-pyrazolyl)-benzoxazoles using hypervalent iodine mediated oxidative cyclization of Schiff’s bases. Molecules 11:43–48CrossRefPubMedGoogle Scholar
  27. Qin M, Wang T, Xu B, Ma Z, Jiang N, Xie H, Gong P, Zhao Y (2015) Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant. Eur J Med Chem 104:115–126CrossRefPubMedGoogle Scholar
  28. Raffa D, Maggio B, Raimondi MV, Cascioferro S, Plescia F, Cancemi G, Daidone G (2015) Recent advanced in bioactive systems containing pyrazole fused with a five membered heterocycle. Eur J Med Chem 97:732–746CrossRefPubMedGoogle Scholar
  29. Sharma M, Chauhan K, Shivahare R, Vishwakarma P, Suthar MK, Sharma A, Gupta S, Saxena JK, Lal J, Chandra P, Kumar B, Chauhan PMS (2013) Discovery of a new class of natural product-inspired quinazolinone hybrid as potent antileishmanial agents. J Med Chem 56:4374–4392CrossRefPubMedGoogle Scholar
  30. Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E (2012) Cancer treatment and survivorship statistics. CA Cancer J Clin 62:220–241CrossRefPubMedGoogle Scholar
  31. Singh N, Pandey SK, Anand N, Dwivedi R, Singh S, Sinha SK, Chaturvedi V, Jaiswal N, Srivastava AK, Shah P, Siddiqui MI, Tripathi RP (2011) Synthesis, molecular modeling and bio-evaluation of cycloalkyl fused 2-aminopyrimidines as antitubercular and antidiabetic agents. Bioorg Med Chem Lett 21:4404–4408CrossRefPubMedGoogle Scholar
  32. Singh S, Punia V, Sharma C, Aneja KR, Prakash O, Pundeer R (2015) A facile synthesis of some new 1-benzothiazolyl-3-aryl/hetaryl-5-(3-aryl-1-phenyl-4-pyrazolyl) pyrazoles and their antimicrobial activity. J Heterocycl Chem 52:1817–1822CrossRefGoogle Scholar
  33. Thanh ND, Mai NTT (2009) Synthesis of N-tetra-O-acetyl-β-D-glucopyranosyl- Nʹ-(4ʹ,6ʹ-diarylpyrimidin-2ʹ-yl)thioureas. Carbohydr Res 344:2399CrossRefPubMedGoogle Scholar
  34. Undare SS, Valekar NJ, Patravale AA, Jamale DK, Vibhute SS, Walekar LS, Kolekar GB, Deshmukh MB, Anbhule PV (2016) Synthesis, anti-inflammatory, ulcerogenic and cyclooxygenase activities of indenopyrimidine derivatives. Bioorg Med Chem Lett 26:814–818CrossRefPubMedGoogle Scholar
  35. van Loevezijn A, Venhorst J, Iwema Bakker WI, de Korte CG, de Looff W, Verhoog S, van Wees JW, van Hoeve M, van de Woestijne RP, van der Neut MA, Borst AJ, van Dongen MJ, de Bruin NM, Keizer HG, Kruse CG (2011) N’-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT6R) antagonists with unique structural features. J Med Chem 54:7030–7054CrossRefPubMedGoogle Scholar
  36. Viveka S, Dinesha, Shama P, Nagaraja GK, Ballav S, Kerkar S (2015) Design and synthesis of some new pyrazolyl-pyrazolines as potential anti-inflammatory, analgesic and antibacterial agents. Eur J Med Chem 101:442–451CrossRefPubMedGoogle Scholar
  37. Williams CS, Watson AJ, Sheng H, Helou R, Shao J, DuBois RN (2000) Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models. Cancer Res 60:6045–6051PubMedGoogle Scholar
  38. Wu Q, Yang Z, Nie Y, Shi Y, Fan D (2014) Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett 347:159–166CrossRefPubMedGoogle Scholar
  39. Yadlapalli RK, Chourasia OP, Vemuri K, Sritharan M, Perali RS (2012) Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group. Bioorg Med Chem Lett 22:2708–2711CrossRefPubMedGoogle Scholar
  40. Yang C, Li J, Zhou R, Chen X, Gao Y, He Z (2015) Facile synthesis of spirooxindole-pyrazolines and spirobenzofuranone-pyrazolines and their fungicidal activity. Org Biomol Chem 13:4869–4878CrossRefPubMedGoogle Scholar
  41. Zhang W-M, Xing M, Zhao T-T, Ren Y-J, Yang X-H, Yang Y-S, Lv P-C, Zhu H-L (2014) Synthesis, molecular modeling and biological evaluation of cinnamic acid derivatives with pyrazole moieties as novel anticancer agents. RSC Adv 4:37197–37207CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of ChemistryJamia Millia Islamia (A Central University)Jamia NagarIndia
  2. 2.Applied Science & Humanities Section, University Polytechnic, Jamia Millia Islamia (A Central University)Jamia NagarIndia
  3. 3.Department of PharmacySchool of Medical & Allied Science, Galgotias UniversityGreater NoidaIndia
  4. 4.Product Development Cell, National Institute of ImmunologyNew DelhiIndia

Personalised recommendations