Skip to main content

Advertisement

SpringerLink
Log in

p-Toluenesulfonic acid-catalyzed solvent-free synthesis and biological evaluation of new 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives

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

Abstract

A solvent-free quick synthesis of 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazoles (3) was accomplished by grinding 2-hydrazino-4,6-dimethylpyrimidine (1) and β-ketonitriles (2) in the presence of p-Toluenesulfonic acid as a catalyst. Subsequently, 5-aminopyrazoles (3) were converted to their corresponding N-acetamide (4) and N-trifluoroacetamide (5) derivatives by treating (3) with acetic anhydride/acetic acid and trifluoroacetic anhydride/trifluoroacetic acid, respectively. The newly synthesized compounds were fully characterized using IR, NMR (1H, 13C, and 19F), mass spectral studies, and elemental analyses. All of the fifteen compounds were screened for their in vitro antibacterial activity against two Gram-positive and two Gram-negative pathogenic bacteria such as Bacillus pumilus, Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli, respectively. Additionally, nine of these compounds were screened for their cytotoxicity against the human Caucasian promyelocytic leukemia (HL-60) cell line using the alamarBlue® assay. Preliminary results reveal that compounds 3a, 3b, 3d, 5a, and 5d are showing moderate-to-significant cytotoxic and antibacterial activity.

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
Fig. 2

Similar content being viewed by others

References

  • Abdel-Aziz M, Abuo-Rahma G, El-Din A, Hassan AA (2009) Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur J Med Chem 44:3480–3487

    Article  CAS  PubMed  Google Scholar 

  • Abu Almaati TM, El-Taweel FM (2004) New trends in the chemistry of 5-aminopyrazoles. J Heterocycl Chem 41:109–134

    Article  Google Scholar 

  • Aggarwal R, Kumar V, Kumar R (2007) A facile and rapid one-pot synthesis of 1,4-diaryl-2-mercaptoimidazoles under solvent-free conditions. J Sulfur Chem 28:617–623

    Article  CAS  Google Scholar 

  • Aggarwal R, Kumar V, Kumar R, Singh SP (2011) Approaches towards the synthesis of 5-aminopyrazoles. Beilstein J Org Chem 7:179–197

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • An H, Eum S, Koh M, Lee SK, Park SB (2008) Diversity-oriented synthesis of privileged benzopyranyl heterocycles from s-cis-Enones. J Org Chem 73:1752–1761

    Article  CAS  PubMed  Google Scholar 

  • Banks JW, Batsanov AS, Howard JAK, O’Hagan D, Rzepa HS, Santamaria SM (1999) The preferred conformation of α-fluoroamides. J Chem Soc Perkin Trans 2:2409–2411

    Article  Google Scholar 

  • Barril X, Beswick MC, Collier A, Drysdale MJ, Dymock BW, Fink A, Grant K, Howes R, Jordan AM, Massey A, Wayne AS, Workman JP, Wright L (2006) 4-Amino derivatives of the Hsp90 inhibitor CCT018159. Bioorg Med Chem Lett 16:2543–2548

    Article  CAS  PubMed  Google Scholar 

  • Benaamane N, Nedjar-Kolli B, Bentarzi Y, Hammal L, Geronikaki A, Eleftheriou P, Langunin A (2008) Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems. Bioorg Med Chem 6:3059–3066

    Article  Google Scholar 

  • Burley SK, Petsko GA (1988) Weakly polar interactions in proteins: advances in protein chemistry. Academic Press, New York, pp 125–189

    Google Scholar 

  • Danagulyan GG, Balasanyan NG, Terent’ev PB, Zalinyan MG (1989) Chemistry of heterocyclic compounds. Kluwer, New York, pp 1369–1373

    Google Scholar 

  • Das J, Moquin RV, Dyckman AJ, Li T, Pitt S, Zhang R, Shen DR, McIntyre KW, Gillooly K, Doweyko AM, Newitt JA, Sack JS, Zhang H, Kiefer SE, Kish K, McKinnon M, Barrish JC, Dodd JH, Schieven GL, Leftheris K (2010) 5-Amino-pyrazoles as potent and selective p38a inhibitors. Bioorg Med Chem Lett 20:6886–6889

    Article  CAS  PubMed  Google Scholar 

  • Dymock BW, Barril X, Brough PA, Cansfield JE, Massey A, McDonald E, Hubbard RE, Surgenor A, Roughley SD, Webb P, Workman P, Wright L, Drysdale MJ (2005) Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem 48:4212–4215

    Article  CAS  PubMed  Google Scholar 

  • El-gazzar ABA, Hussein HAR, Hafez HN (2007) Synthesis and biological evaluation of thieno[2,3-d]pyrimidine derivatives for anti-inflammatory, analgesic and ulcerogenic activity. Acta Pharm 57:395–411

    Article  CAS  PubMed  Google Scholar 

  • Farag AM, Mayhoub AS, Barakat SE, Bayomi AH (2008) Regioselective synthesis and antitumor screening of some novel N-phenylpyrazole derivatives. Bioorg Med Chem 16:881–889

    Article  CAS  PubMed  Google Scholar 

  • Gakhar HK, Gill GS, Multani JS (1971) Thiopegan derivatives part XLIX. J Indian Chem Soc 48:953–956

    CAS  Google Scholar 

  • Gilbert AM, Failli A, Shumsky J, Yang Y, Severin A, Singh G, Hu W, Keeney D, Petersen PJ, Katz AH (2006) Pyrazolidine-3,5-diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase. J Med Chem 49:6027–6036

    Article  CAS  PubMed  Google Scholar 

  • Goldstein DM, Kuglstatter YL, Soth MJ (2009) Selective p38r inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J Med Chem 53:2345–2353

    Article  Google Scholar 

  • Gopalsamy A, Yang H, Ellingboe JW, Tsou HR, Zhang N, Honores E, Powell D, Miranda M, McGinnis JP, Rabindran SK (2005) Pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides as novel anti-proliferative agents: parallel synthesis for lead optimization of amide region. Bioorg Med Chem Lett 15:1591–1594

    Article  CAS  PubMed  Google Scholar 

  • Hayakawa M, Kaizawa H, Moritomo H, Koizumi T, Ohishi T, Okada M, Ohta M, Tsukamoto S, Parker P, Workman P, Waterfield M (2006) Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors. Bioorg Med Chem 14:6847–6858

    Article  CAS  PubMed  Google Scholar 

  • Heffron TP, Berry M, Castanedo G et al (2010) Identification of GNE-477, a potent and efficacious dual PI3 K/mTOR inhibitor. Bioorg Med Chem Lett 20:2408–2411

    Article  CAS  PubMed  Google Scholar 

  • Hiraku Y, Oikawa S, Kawanishi S (2002) Distamycin A, a minor groove binder, changes enediyne-induced DNA cleavage sites and enhances apoptosis. Nucl Acids Res Suppl 2:95–96

    Article  CAS  Google Scholar 

  • Jung JC, Walkins EB, Avery MA (2002) Synthesis of 3-substituted and 3,4-disubstituted pyrazolin-5-ones. Tetrahedron 58:3639–3646

    Article  CAS  Google Scholar 

  • Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D, Sliwkowski MX (2009) Ligand-independent HER2/HER3/PI3 K complex is disrupted by trastuzumab and is effectively inhibited by the PI3 K inhibitor GDC-0941. Cancer Cell 15:429–440

    Article  CAS  PubMed  Google Scholar 

  • Kaiko RF, Wallenstein SL, Rogers AG, Grabinski PY, Houde RW (1981) Analgesic and mood effects of heroin and morphine in cancer patients with postoperative pain. N Engl J Med 304:1501–1505

    Article  CAS  PubMed  Google Scholar 

  • Kane JL, Hirth BH, Laing O, Gourlie BB, Nahill S, Barsomiam G (2003) Ureas of 5-aminopyrazole and 2-aminothiazole inhibit growth of gram-positive bacteria. Bioorg Med Chem Lett 13:4463–4466

    Article  CAS  PubMed  Google Scholar 

  • Kordik CP, Luo C, Zanoni BC, Dax SL, McNally JJ, Lovenberg TW, Wilson SJ, Reitz AB (2001) Aminopyrazoles with high affinity for the human neuropeptide Y5 receptor. Bioorg Med Chem Lett 11:2283–2286

    Article  CAS  PubMed  Google Scholar 

  • Kumar V, Aggarwal R, Tyagi P, Singh SP (2005) Synthesis and antibacterial activity of some new 1-heteroaryl-5-amino-4-phenyl-3-trifluoromethylpyrazoles. Eur J Med Chem 40:922–927

    Article  CAS  PubMed  Google Scholar 

  • Kumar V, Aggarwal R, Tyagi P, Singh SP (2006) Synthesis and antibacterial activity of some new 1-heteroaryl-5-amino-3H/methyl-4-phenylpyrazoles. Bioorg Med Chem 14:1785–1791

    Article  PubMed  Google Scholar 

  • Lee KY, Kim JM, Kim JN (2003) Regioselective synthesis of 1,3,4,5-tetrasubstituted pyrazoles from Baylis–Hillman adducts. Tetrahedron Lett 44:6737–6740

    Article  CAS  Google Scholar 

  • Lindvall M, McBride C, McKenna M, Gesner TG, Yabannavar A, Wong K, Lin S, Walter A, Shafer CM (2011) 3D pharmacophore model-assisted discovery of novel CDC7 inhibitors. Med Chem Lett 2:720–723

    Article  CAS  Google Scholar 

  • Liu XH, Cui P, Song BA, Bhadury PS, Zhu HL, Wang SF (2008) Synthesis, structure and antibacterial activity of novel 1-(5-substituted-3-substituted-4,5-dihydropyrazol-1-yl)ethanone oxime ester derivatives. Bioorg Med Chem 16:4075–4082

    Article  CAS  PubMed  Google Scholar 

  • Manetti F, Brullo C, Magnani M, Mosci F, Chelli B, Crespan E, Schenone S, Naldini A, Bruno O, Trincavelli ML, Maga G, Carraro F, Martini C, Bondavalli F, Botta M (2008) Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines. J Med Chem 51:1252–1259

    Article  CAS  PubMed  Google Scholar 

  • Meegalla SK, Doller D, Sha DY, Soll R, Wisnewski N, Silverb GM, Dhanoaa D (2004) Synthesis and GABA receptor potency of 3-thiomethyl-4-(hetero)aryl-5-amino-1-phenylpyrazoles. Bioorg Med Chem Lett 14:4949–4953

    Article  CAS  PubMed  Google Scholar 

  • Mercep M, Mesic M, Pesic D (2004) PCT Int Appl WO 03 99, 822. Chem Abstr 140:16724j

  • Michon V, Hervé du Penhoat C, Tombret F, Gillardin JM, Lepage F, Berthon L (1995) Preparation, structural analysis and anticonvulsant activity of 3- and 5-aminopyrazole N-benzoyl derivatives. Eur J Med Chem 30:147–155

    Article  CAS  Google Scholar 

  • Okunji CO, Okeke CN, Gugnani HC, Iwu MM (1990) An antifungal Spirostanol Saponin from Fruit Pulp of Dracaena mannii. Int J Crude Drug Res 28:193–199

    CAS  Google Scholar 

  • Perez C, Pauli M, Bezerque P (1990) An antibiotic assay by the agar-well diffusion method. J Aotabiol 15:113–115

    Google Scholar 

  • Rios JL, Recio MC, Vilar (1988) A. Screening methods for natural products with antimicrobial activity: a review of the literature. J Ethnopharmacol 23:127–149

    Article  CAS  PubMed  Google Scholar 

  • Sellery S, Gratteri P, Costagli C, Bonaccini C, Coztanzo A, Melani F, Guerrini G, Ciciani G, Costa B, Spinetti F, Martini C, Bruni F (2005) Insight into 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides as peripheral benzodiazepine receptor ligands: synthesis, biological evaluation and 3D-QSAR investigation. Bioorg Med Chem 13:4821–4834

    Article  Google Scholar 

  • Sherif AFR (2006) Synthesis and in vitro antitumor evaluation of some indeno[1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems. Bioorg Med Chem 14:6475–6485

    Article  Google Scholar 

  • Shetty NS, Lamani RS, Khazi IM (2009) Synthesis and antimicrobial activity of some novel thienopyrimidines and triazolothinopyrimidines. J Chem Sci 121:301–307

    Article  CAS  Google Scholar 

  • Soliman R, Darwish SAS (1983) Antidiabetic activity of some 1-substituted 3,5-dimethylpyrazoles. J Med Chem 26:1659–1663

    Article  CAS  PubMed  Google Scholar 

  • Studzinski GP, Bhandal AK, Brelvi ZS (1986) Potentiation by 1-α,25-dihydroxyvitamin D3 of cytotoxicity to HL-60 cells produced by cytarabine and hydroxyurea. J Natl Cancer Inst 76(4):641–648

    CAS  PubMed  Google Scholar 

  • Wei F, Zhao B, Huang B, Zhang L, Sun C, Dong W, Shin D, Miao J (2006) Design, synthesis, and preliminary biological evaluation of novel ethyl 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate. Bioorg Med Chem Lett 16:6342–6347

    Article  CAS  PubMed  Google Scholar 

  • Zhao W, Zhang T, Qu B, Wu X, Zhu X, Meng F, Gu Y, Shu Y, Shen Y, Sun Y, Xu Q (2011) Sorafenib induces apoptosis in HL60 cells by inhibiting Src kinase-mediated STAT3 phosphorylation. Anticancer Drugs 22(1):79–88

    Article  CAS  PubMed  Google Scholar 

  • Zoltewicz JA, Uray G (1994) Thiamin: a critical evaluation of recent chemistry of the pyrimidine ring. Bioorg Chem 22:1–28

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We (RA and IR) thank the Department of Science and Technology, New Delhi, India, and Trinity College, Dublin, Ireland, for providing financial assistance under India–Ireland Cooperative Science Programme. Anshul Bansal is thankful to the Council of Scientific and Industrial Research, New Delhi, India, for Senior Research Fellowship. Elena Diez-Cecilia thanks IRCSET (Ireland) for financial support.

Author information

Authors and Affiliations

  1. Department of Chemistry, Kurukshetra University, Kurukshetra, 136 119, India

    Ranjana Aggarwal & Anshul Bansal

  2. Trinity Biomedical Sciences Institute, School of Chemistry, Trinity College Dublin, 154-160 Pearse St., Dublin 2, Ireland

    Isabel Rozas & Elena Diez-Cecilia

  3. Department of Biotechnology, Kurukshetra University, Kurukshetra, 136 119, India

    Amanjot Kaur, Ritu Mahajan & Jitender Sharma

Authors
  1. Ranjana Aggarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anshul Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Isabel Rozas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena Diez-Cecilia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amanjot Kaur
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ritu Mahajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jitender Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ranjana Aggarwal.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 615 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Aggarwal, R., Bansal, A., Rozas, I. et al. p-Toluenesulfonic acid-catalyzed solvent-free synthesis and biological evaluation of new 1-(4′,6′-dimethylpyrimidin-2′-yl)-5-amino-4H-3-arylpyrazole derivatives. Med Chem Res 23, 1454–1464 (2014). https://doi.org/10.1007/s00044-013-0751-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-013-0751-9

Keywords

Search

Navigation