Skip to main content

Advertisement

SpringerLink
Log in

Design, synthesis and anti-cancer evaluation of a novel series of pyrazolo [1, 5-a] pyrimidine substituted diamide derivatives

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

A novel series of pyrazolo [1, 5-a] pyrimidine substituted diamides has been designed and synthesized using a linear mode multistep synthesis. The synthesized compounds were characterized by 1H NMR, 13C NMR, ESI-MS and IR analyses. These new compounds were screened for their in vitro antiproliferative activity using an MTT assay. Out of 23 derivatives synthesized in the current study, compounds 10q, 10u and 10w showed good anticancer activity against HeLa cell line. Furthermore, these derivatives gave IC50 values of less than 10 µM against HeLa cell and were therefore more potent than the marketed anticancer drug cis-platin (17.83 µM).

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3

Similar content being viewed by others

References

  • Ali HI, Fujita T, Akaho E, Nagamatsu T (2010) A comparative study of autodock and PMF scoring perform ances, and SAR of 2-substituted pyrazolotriazolopyrimidines and 4-substituted pyrazolopyrimidines as potent xanthine oxidase inhibitors. J Comput Aided Mol Des 24(1):57–75

    Article  CAS  PubMed  Google Scholar 

  • Aly AA (2006) Synthesis of polyfunctionally substituted pyrazolonaphthyridine, pentaza naphthalene and heptaazaphenanthrene derivatives. Phosphorus Sulfur Silicon Relat Elem 181(10):2395–2409

    Article  CAS  Google Scholar 

  • Austen MA, John KN, Henri JF, George BA(2001) Qinazoline derivatives and their use as pharmaceuticals.WO2001021596

  • Bagley MC, Baashen M, Paddock VL, Kipling D, Davis T (2013) Regiocontrolled synthesis of 3- and 5-amino pyrazoles, pyrazolo [3, 4-d] pyrimidines, pyrazolo [3, 4-b] pyridines and pyrazolo [3, 4- b] quinolinones as MAPK inhibitors. Tetrahedron 69(39):8429–8438

    Article  CAS  Google Scholar 

  • Bakavoli M, Bagherzadeh G, Vaseghifar M, Shiri A, Pordel M, Mashreghi M, Pordeli P, Araghi M (2010) Molecular iodine promoted synthesis of new pyrazolo [3, 4-d] pyrimidine derivatives as potential antibacterial agents. Eur J Med Chem 45(2):647–650

    Article  CAS  PubMed  Google Scholar 

  • Chauhan M, Kumar R (2013) Medicinal attributes of pyrazolo [3, 4-d] pyrimidines: a Review. Bioorg Med Chem 21(18):5657–5668

    Article  CAS  PubMed  Google Scholar 

  • Chiruvella KK, Kari V, Choudhary B, Nambiar M, Ghanta RG, Raghavan SC (2008) Methyl angolensate, a natural tetranortriterpenoid induces intrinsic apoptotic pathway in leukemic cells. FEBS Lett 582(29):4066–4076

    Article  CAS  PubMed  Google Scholar 

  • Curran KJ, Verheijen JC, Kaplan J, Richard DJ, Toral-Barza L, Hollander I, Lucas J, Ayral–Kaloustian S, Yu K, Zask A (2010) Pyrazolopyrimidines as highly potent and selective, ATP- competitive inhibitors of the mammalian target of rapamycin (mTOR): Optimization of the 1- substituent. Bioorg Med Chem Lett 20(4):1440–1444

    Article  CAS  PubMed  Google Scholar 

  • Dinakaran VS, Bomma B, Srinivasan KK (2012) Fused pyrimidines: The heterocycle of diverse biological and pharmacological significance. Der Pharma Chem 4(1):255 –265

    CAS  Google Scholar 

  • Edmondson JM, Armstrong LS, Martinez AO (1988) A rapid and simple MTT-based spectro photometric assay for determining drug sensitivity in monolayer cultures. J Tissue Cult Methods 11:15–17

    Article  CAS  Google Scholar 

  • El-Sherief HA, Mahmoud AM, Ismaiel AA (1997) Studies on the synthesis and cyclization reactions of 2- (5-Amino-3-Arylpyrazol-1-yl)-3-methylquinoxalines. J Chem Res 9:322–323

    Article  Google Scholar 

  • Ge M, Cline E, Yang L (2006) A general method for the preparation of 3-acyl-4-cyano-5-amino- pyrazoles. Tetrahedron Lett 47(32):5797–5799

    Article  CAS  Google Scholar 

  • Gonclaves MST, Oliveira-Campos AMF, Rodrigues LM, Proenca MFRP (2012) Synthesis of 4-Amino- 3, 5- dicyano-arylpyrazoles. Part 2: Isolation and characterization of by-products. Synth Commun 42(11):1695–1703

    Article  Google Scholar 

  • Gopalaswamy A, Ciszewski G, Hu Y, Lee F, Feldberg L, Frommer E, Kim S, Collins K, Wojciechowicz D, Mallon R (2009) Identification of pyrazolo [1, 5-a] pyrimidine-3-carboxylates as B-Raf kinase inhibitors. Bioorg Med Chem Lett 19:2735–2738

    Article  Google Scholar 

  • Gouhar RS, Fathalla OA, Abd El-Karim SS (2013) Synthesis and anticancer screening of some novel substituted pyrazole derivatives. Der Pharma Chemica 5(6):225–233

    Google Scholar 

  • Hardtmann GE, Koletar G, Pfister OR, Gogerty JH, Iorio LC (1975) Synthesis and biological evaluation of some 10-substituted -2, 3-dihydroimidazo [2, 1-b] quinazolin-5[10H]-ones, a new class of bronchodilators. J Med Chem 18(5):447–453

    Article  CAS  PubMed  Google Scholar 

  • Hartwig JF, Motoi K, Hauck SI, Shaughnessy KH, Alcazar- Roman LM (1999) Room- temperature palladium catalyzed amination of aryl bromides and chlorides and extended scope of aromatic C- N bond formation with a commercial ligand. J Org Chem 64(15):5575 –5580

    Article  CAS  PubMed  Google Scholar 

  • Hillebrand S, Tsuchiya T, Hoffman S, Cristau P, Wasnaire P, Seitz T, Benting J, Wachendorff- Neumann U, Schmidt PJ (2014) Piperidine pyrazoles as fungicides. US 20140228404 A1

  • Kamal El-Dean AM, Elkhawaga AM, Radwan ShM, Ahmed MM (2009) Synthesis of some pyridotheinopyrazolo pyrimido pyrimidine and mercaptomethylpyrazolopyrimidine derivatives. Phosphorous Sulfur Silicon Relat Elem 184(8):2034–2048

    Article  Google Scholar 

  • Kim I, Song JH, Park CM, Jeong JW, Kim HR, Ha JR, No Z, Hyun YL, Cho YS, Kang NS, Jeon DJ (2010) Design, synthesis and evaluation of 2-aryl-7- (3’, 4’- Dialkoxy phenyl)-pyrazolo [1, 5-a] pyrimidines as novel PDE -4 inhibitors. Bioorg Med Chem Lett 20(3):922–926

    Article  CAS  PubMed  Google Scholar 

  • Ley SV, Thomas AW (2003) Modern synthetic methods for copper-mediated C (aryl)-O, C (aryl)-N and C (aryl) -S bond formation. Angew Chem Int Ed 42(44):5400–5449

    Article  CAS  Google Scholar 

  • Louie J, Hartwig JF (1995) Palladium—catalyzed synthesis of aryl amines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett 36(21):3609–3612

    Article  CAS  Google Scholar 

  • Maeda H, Akaike T, Miyamoto Y, Yoshida M (1997) Pyrazolopyrimidines as antihyperten sive agents. EP 0759298 A2

  • Nag S, Mishra A, Batra S (2008) A facile route to the synthesis of pyrimido [2, 1-b] quina zoline core from the primary allyl amines afforded from Baylis—Hilman adducts. Tetrahedron 64(44):10162–10171

    Article  CAS  Google Scholar 

  • Nitulescu GM, Paunescu H, Draghici C, Missir AV, Coman OA, Fulga I (2010) Synthesis and pharmacological evaluation of some new pyrazole derivatives. Farmacia 58(2):190 –197

    CAS  Google Scholar 

  • Oslob JD, Romanowski MJ, Allen DA, Baskaran S, Bui M, Elling RA, Flanagan WM, Fung AD, Hanan EJ, Harris S, Heumann SA, Hoch U, Jacobs JW, Lam J, Lawrence CE, McDowell RS, Nannini MA, Shen W, Silverman JA, Sopko MM, Tangonan BT, Teague J, Yoburn JC, Yu CH, Zhong M, Zimmerman KM, O’Brien T, Lew W (2008) Discovery of a potent and selective Aurora kinase inhibitor. Bioorg Med Chem Lett 18(17):4880–4884

    Article  CAS  PubMed  Google Scholar 

  • Prasad KN, Ashok G, Raghu C, Shivamurthy GR, Vijayan P, Ardhya SM (2005) In vitro cytotoxic properties of Ipomoea aquatic leaf. Indian J Pharmacol 37(6):397–398

    Article  Google Scholar 

  • Rashad AE, Hegab MI, Abdel–Megeid RE, Fathalla N, Abdel-Megeid FME (2009) Synthesis and anti –HSV-1-evaluation of some pyrazoles and fused pyrazolopyrimidines. Eur J Med Chem 44(8):3285–3292

    Article  CAS  PubMed  Google Scholar 

  • Schenone S, Brullo C, Bruno O, Bondavalli F, Mosti L, Maga G, Crespan E, Carraro F, Manetti F, Tintori C, Botta M (2008) Synthesis, biological evaluation and docking studies of 4- amino substituted 1H- pyrazolo [3, 4-d] pyrimidines. Eur J Med Chem 43(12):2665–2676

    Article  CAS  PubMed  Google Scholar 

  • Soliman AMM, Abd El-Aleem M, El-Remaily AA, Sultan AA, Abdel-Ghany H (2014) Synthesis of some novel imidazopyrazole and pyrazolopyrimidine derivatives. J Heterocyclic Chem 51(5):1476 –1481

    Article  CAS  Google Scholar 

  • Suzuki F, Kuroda T, Nakasato Y, Manabe H, Ohmori K, Kitamura S, Ichikawa S, Ohno T (1992) New Bronchodilators. 1. 1, 5- substituted 1H-imidazo [4, 5-c] quinolin-4[5H]-ones. J Med Chem 35(22):4045–4053

    Article  CAS  PubMed  Google Scholar 

  • Vijesh AM, Isloor AM, Shetty P, Sundershan S, Fun HK (2013) New pyrazole derivatives containing 1, 2, 4-triazoles and benzoxazoles as potent antimicrobial and analgesic agents. Eur J Med Chem 62:410–415

    Article  CAS  PubMed  Google Scholar 

  • Wu Z, Hu D, Kuang J, Cai H, Wu S, Xue W (2012) Synthesis and antifungal activity of N-(substituted pyridin yl)-1-methyl (phenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives. Molecules 17:14205–14218

    Article  CAS  PubMed  Google Scholar 

  • Xin J, Uttamapinant C, Ting AY (2011) Synthesis of 7-Aminocoumarin by Buchwald—Hartwig cross coupling for specific protein labeling in living cells. Chem Bio Chem 12(1):65–70

    Article  Google Scholar 

  • Yoo J, Thai KM, Kim DK, Lee JY, Park HJ (2007) 3D- QSAR studies on sildenafil analogues, selective phosphodiesterase 5 inhibitors. Bioorg Med Chem Lett 17(15):4271–4274

    Article  CAS  PubMed  Google Scholar 

  • Yuan J, Gulianello M, Lombeert SD, Brodbeck R, Kieltyka A, Hodgetts KJ (2002) 3-Aryl pyrazolo [4, 3-d] pyrimidine derivatives: nonpeptide CRF-1 antagonists. Bioorg Med Chem Lett 12(16):2133–2136

    Article  CAS  PubMed  Google Scholar 

  • Zhang X, Song Y, Gao L, Guo X, Fan X (2014) Highly facile and region- selective synthesis of pyrazolo [1, 5-a] pyrimidines via reactions of 1,2-allenic ketones with aminopyrazoles. Org Biomol Chem 12(13):2099–2107

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the Management Team at Anthem Biosciences Pvt. Ltd., Bangalore, India, for their valuable support and allocation of proper resources to allow for the completion of this work. We would also like to thank the Analytical Chemistry Team at the Department of Analytical Chemistry, Anthem Biosciences, Bangalore, India, for carried out all the analytical work mentioned in this study. Finally, we would like to thank the Molecular Biology Team at the Maratha Mandal Institute of Technology, Belagavi, Karnataka, India, for conducting the anti-proliferative studies by MTT assay.

Author information

Authors and Affiliations

  1. Anthem Biosciences Pvt. Ltd. 49, Bommasandra Industrial Area, Bommasandra, Bangalore, 560 099, Karnataka, India

    A.K. Ajeesh Kumar, Peter Serjious Lakra & Ganesh Sambasivam

  2. Department of PG Studies and Research in Industrial Chemistry, School of Chemical Sciences, Kuvempu University, Shankaraghatta, Shimoga, Karnataka, 577 451, India

    Yadav D. Bodke

  3. Department of Microbiology, Maratha Mandal’s NGH Institute of Dental Sciences & Research Centre, Belgaum, Karnataka, 590 010, India

    Kishore G. Bhat

Authors
  1. A.K. Ajeesh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yadav D. Bodke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Serjious Lakra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ganesh Sambasivam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kishore G. Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A.K. Ajeesh Kumar.

Ethics declarations

Conflict of interests

The authors declare no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ajeesh Kumar, A., Bodke, Y.D., Lakra, P.S. et al. Design, synthesis and anti-cancer evaluation of a novel series of pyrazolo [1, 5-a] pyrimidine substituted diamide derivatives. Med Chem Res 26, 714–744 (2017). https://doi.org/10.1007/s00044-016-1770-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-016-1770-0

Keywords

Search

Navigation