Download PDF
Drug Res (Stuttg) 2013; 63(03): 121-128
DOI: 10.1055/s-0032-1333275
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Cytotoxic Activities of some Novel Benzhydrylpiperazine Derivatives

E. E. Gurdal
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey
,
M. Yarim
1   Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey
,
I. Durmaz
2   Department of Molecular Biology and Genetics, BilGen, Genetics and Biotechnology Research Center, Faculty of Science, Bilkent University, Ankara, Turkey
,
R. Cetin-Atalay
2   Department of Molecular Biology and Genetics, BilGen, Genetics and Biotechnology Research Center, Faculty of Science, Bilkent University, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

received 27 November 2012

accepted 20 December 2012

Publication Date:
11 February 2013 (online)

Also available at
    Permissions and Reprints

Abstract

This study presents the synthesis of nineteen 1-(substitutedbenzoyl)-4-benzhydrylpiperazine and 1-[(substitutedphenyl)sulfonyl]-4-benzhydrylpiperazine derivatives. In vitro cytotoxic activities of the compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines by sulphorhodamine B assay. Among the test compounds, benzamide derivatives had high cytotoxic activity whereas sulfonamide derivatives showed variable 50% growth inhibition (GI50).

Key words

benzhydrylpiperazine - benzoyl chloride - sulfonyl chloride - cytotoxicity - sulphorhodamine B
 

  • References

  • 1 Albro LP, Baltzly R, Phillips AP. Unsymmetrically disubstituted piperazines II. Histamine antagonists. J Org Chem 1949; 14: 771-774
    CrossrefPubMedGoogle Scholar
  • 2 Baltzly R, DuBreuil S, Ide WS et al. Unsymmetrically disubstituted piperazines III. N-methyl-N'-benzhydrylpiperazines as histamine antagonists. J Org Chem 1949; 14: 775-782
    CrossrefPubMedGoogle Scholar
  • 3 Iemura R, Kawashima T, Fukuda T et al. Synthesis of 2-(4-substituted-1-piperazinyl)benzimidazoles as H1-antihistaminic agents. J Med Chem 1986; 29: 1178-1183
    CrossrefPubMedGoogle Scholar
  • 4 Beck K, Hamlin K, Weston A. Histamine antagonists. IV. C-methyl derivatives of 1,4-disubstituted piperazines. J Am Chem Soc 1952; 74: 605-608
    CrossrefPubMedGoogle Scholar
  • 5 Vandenberk J, Kennis L, Van der Aa M et al. Piperazine derivatives, US-4250176 1981
    PubMed
  • 6 Wang L, Wang T, Yang B et al. Design, synthesis, and anti-allergic activities of novel (R)(-)-1-[(4-chlorophenyl)phenylmethyl]piperazine derivatives. Med Chem Res 2010; 21: 124-132
    PubMedGoogle Scholar
  • 7 Zamponi G, Feng Z, Zhang L et al. Scaffold-based design and synthesis of potent N-type calcium channel blockers. Bioorg Med Chem Lett 2009; 19: 6467-6472
    CrossrefPubMedGoogle Scholar
  • 8 Alps B. Drugs acting on calcium channels – potential treatment for ischemic stroke. Brit J Clin Pharmaco 1992; 34: 199-206
    CrossrefPubMedGoogle Scholar
  • 9 Miyake N, Fujita R, Ishikawa M et al. Reversal of multidrug resistance in human leukemia K562 by tamolarizine, a novel calcium antagonist. Jpn J Pharmacol 2000; 82: 265-268
    CrossrefPubMedGoogle Scholar
  • 10 Kimura M, Masuda T, Yamada K et al. Novel diphenylalkyl piperazine derivatives with dual calcium antagonistic and antioxidative activities. Bioorg Med Chem Lett 2002; 12: 1947-1950
    CrossrefPubMedGoogle Scholar
  • 11 Pajouhesh H, Feng Z, Ding Y et al. Structure-activity relationships of diphenylpiperazine N-type calcium channel inhibitors. Bioorg Med Chem Lett 2010; 20: 1378-1383
    CrossrefPubMedGoogle Scholar
  • 12 Kam Y, Rhee H, Rhim H et al. Synthesis and T-type calcium channel blocking activity of novel diphenylpiperazine compounds, and evaluation of in vivo analgesic activity. Bioorg Med Chem 2010; 18: 5938-5944
    CrossrefPubMedGoogle Scholar
  • 13 Kurokawa M, Sato F, Hatano N et al. A new class of calcium antagonists. Synthesis and biological activity of 11-[(ω-aminoalkanoyl)amino]-6,6a,7,8,9,10,10a,11-octahydrodibenzo[b,e]thiepin derivatives. J Med Chem 1991; 34: 593-599
    CrossrefPubMedGoogle Scholar
  • 14 Doddareddy M, Choo H, Cho Y et al. 3D pharmacophore based virtual screening of T-type calcium channel blockers. Bioorg Med Chem 2007; 15: 1091-1105
    CrossrefPubMedGoogle Scholar
  • 15 Sasse B, Mach U, Leppaenen J et al. Hybrid approach for the design of highly affine and selective dopamine D-3 receptor ligands using privileged scaffolds of biogenic amine GPCR ligands. Bioorg Med Chem 2007; 15: 7258-7273
    CrossrefPubMedGoogle Scholar
  • 16 Jung J, Jung S, Koh H. Asymmetric synthesis of chiral piperazinylpropylisoxazoline ligands for dopamine receptors. Eur J Med Chem 2007; 42: 1044-1048
    CrossrefPubMedGoogle Scholar
  • 17 Kimura M, Masuda T, Yamada K et al. Synthesis of novel diphenyl piperazine derivatives and their activities as inhibitors of dopamine uptake in the central nervous system. Bioorg Med Chem 2003; 11: 1621-1630
    CrossrefPubMedGoogle Scholar
  • 18 Abou-Gharbia M, Patel UR, Moyer JA et al. Psychotropic agents: Synthesis and antipsychotic activity of substituted β-carbinoles. J Med Chem 1987; 30: 1100-1105
    CrossrefPubMedGoogle Scholar
  • 19 Okachi R, Niino H, Kitaura K et al. Synthesis and antibacterial activity of 2,2′-dithiobis(benzamide) derivatives against Mycobacterium species. J Med Chem 1985; 28: 1772-1779
    CrossrefPubMedGoogle Scholar
  • 20 Punkvang A, Saparpakorn P, Hannongbua S et al. Insight into crucial inhibitor-enzyme interaction of arylamides as novel direct inhibitors of the enoyl ACP reductase (InhA) from Mycobacterium tuberculosis: computer-aided molecular design. Monatsh Chem 2010; 141: 1029-1041
    CrossrefPubMedGoogle Scholar
  • 21 Dinakaran M, Senthilkumar P, Yogeeswari P et al. Antimycobacterial activities of novel 2-(sub)-3-fluoro/nitro-5,12-dihydro-5-oxo-benzothiazolo[3,2-a]quinoline-6-carboxylic acid. Bioorg Med Chem 2008; 16: 3408-3418
    CrossrefPubMedGoogle Scholar
  • 22 Senthilkumar P, Dinakaran M, Banerjee D et al. Synthesis and antimycobacterial evaluation of newer 1-cyclopropyl-1,4-dihydro-6-fluoro-7-(substituted secondary amino)-8-methoxy-5-(sub)-4-oxoquinoline-3-carboxylic acids. Bioorg Med Chem 2008; 16: 2558-2569
    CrossrefPubMedGoogle Scholar
  • 23 Upadhayaya R, Vandavasi J, Kardile R et al. Novel quinoline and naphthalene derivatives as potent antimycobacterial agents. Eur J Med Chem 2010; 45: 1854-1867
    CrossrefPubMedGoogle Scholar
  • 24 Kumar A, Siddiqi MI. Receptor based 3D-QSAR to identify putative binders of Mycobacterium tuberculosis Enoyl acyl carrier protein reductase. J Mol Model 2010; 16: 877-893
    CrossrefPubMedGoogle Scholar
  • 25 Lu XY, Chen YD, You QD. 3D-QSAR studies of arylcarboxamides with inhibitory activity on InhA using pharmacophore-based alignment. Chem Biol Drug Des 2010; 75: 195-203
    CrossrefPubMedGoogle Scholar
  • 26 Sriram D, Senthilkumar P, Dinakaran M et al. Antimycobacterial activities of novel 1-(cyclopropyl/tert-butyl/4-fluorophenyl)-1,4-dihydro-6-nitro-4-oxo-7-(substituted secondary amino)-1,8-naphthyridine-3-carboxylic acid. J Med Chem 2007; 50: 6232-6239
    CrossrefPubMedGoogle Scholar
  • 27 Senthilkumar P, Dinakaran M, Yogeeswari P et al. Synthesis and antimycobacterial activities of novel 6-nitroquinolone-3-carboxylic acids. Eur J Med Chem 2009; 44: 345-358
    CrossrefPubMedGoogle Scholar
  • 28 Kumar A, Siddiqi M. CoMFA based de novo design of pyrrolidine carboxamides as inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis . J Mol Model 2008; 14: 923-935
    CrossrefPubMedGoogle Scholar
  • 29 Lu X, Chen Y, Jiang Y et al. Discovery of potential new InhA direct inhibitors based on pharmacophore and 3D-QSAR analysis followed by in silico screening. Eur J Med Chem 2009; 44: 3718-3730
    CrossrefPubMedGoogle Scholar
  • 30 Muddassar M, Jang J, Gon H et al. Identification of novel antitubercular compounds through hybrid virtual screening approach. Bioorg Med Chem 2010; 18: 6914-6921
    CrossrefPubMedGoogle Scholar
  • 31 Chandra J, Sadashiva C, Kavitha C et al. Synthesis and in vitro antimicrobial studies of medicinally important novel N-alkyl and N-sulfonyl derivatives of 1-[bis(4-fluorophenyl)methyl]piperazine. Bioorg Med Chem 2006; 14: 6621-6627
    CrossrefPubMedGoogle Scholar
  • 32 Verderame M. 1,4-Disubstituted piperazines. 3. Piperazinylbenzothiazoles. J Med Chem 1972; 15: 693-694
    CrossrefPubMedGoogle Scholar
  • 33 Aytemir M, Ozcelik B. A study of cytotoxicity of novel chlorokojic acid derivatives with their antimicrobial and antiviral activities. Eur J Med Chem 2010; 45: 4089-4095
    CrossrefPubMedGoogle Scholar
  • 34 Patel I, Parmar S. Synthesis and studies of novel optically active Schiff’s base derivatives and their antimicrobial activities. E-Journal of Chemistry 2010; 7: 617-623
    PubMedGoogle Scholar
  • 35 Srinivasan S, Gupta S, Marwah R et al. Synthesis, characterization & in vitro biological studies of novel N-aryl piperazinyl fluoroquinolones. Res J Pharm Biol Chem Sci 2010; 1: 208-218
    PubMedGoogle Scholar
  • 36 Shivakumara K, Prakasha K, Gowda D. Synthesis and antimicrobial activity of amino acids conjugated diphenylmethylpiperazine derivatives. E-Journal of Chemistry 2009; 6: 473-479
    PubMedGoogle Scholar
  • 37 Chern J, Shia K, Hsu T et al. Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidinies: a novel class of potent enterovirus inhibitors. Bioorg Med Chem Lett 2004; 14: 2519-2525
    CrossrefPubMedGoogle Scholar
  • 38 Curreli F, Zhang H, Zhang X et al. Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid. Bioorg Med Chem 2011; 19: 77-90
    CrossrefPubMedGoogle Scholar
  • 39 Kumar C, Prasad S, Vinaya K et al. Synthesis and in vitro antiproliferative activity of novel 1-benzhydryl-piperazine derivatives against human cancer cell lines. Eur J Med Chem 2009; 44: 1223-1229
    CrossrefPubMedGoogle Scholar
  • 40 Yarim M, Koksal M, Durmaz I et al. Cancer cell cytotoxicities of 1-(4-substitutedbenzoyl)-4-(4-chlorobenzhydryl)piperazine derivatives. Int J Mol Sci 2012; 13: 8071-8085
    CrossrefPubMedGoogle Scholar
  • 41 Huang W, Liu M, Li Y et al. Design, synthesis and antitumor activity of novel chromone and aurone derivatives. Bioorg Med Chem 2007; 15: 5191-5197
    CrossrefPubMedGoogle Scholar
  • 42 Huang W, Ding Y, Miao Y et al. Synthesis and antitumor activity of novel dithiocarbamate substituted chromones. Eur J Med Chem 2009; 44: 3687-3696
    CrossrefPubMedGoogle Scholar
  • 43 Gan L, Fang B, Zhou C. Synthesis of azole-containing piperazine derivatives and evaluation of their antibacterial, antifungal and cytotoxic activities. B Kor Chem Soc 2010; 31: 3684-3692
    PubMedGoogle Scholar
  • 44 Kumar C, Swamy S, Thimmegowda N et al. Synthesis and evaluation of 1-benzhydryl-sulfonyl-piperazine derivatives as inhibitors of MDA-MB-231 human breast cancer cell proliferation. Med Chem Res 2007; 16: 179-187
    CrossrefPubMedGoogle Scholar
  • 45 Wang W, Xu X, Chen Y et al. Apoptosis of human Burkitt's lymphoma cells induced by 2-N,N-diethylaminocarbonyloxymethyl-1-diphenyl-methyl-4-(3,4,5-trimethoxybenzoyl)piperazine hydrochloride (PMS-1077). Arch Pharm Res 2009; 32: 1727-1736
    CrossrefPubMedGoogle Scholar
  • 46 Demma M, Maxwell E, Ramos R et al. SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem 2010; 285: 198-212
    PubMedGoogle Scholar
  • 47 Venkat-Narsaiah A, Narsimha P. Efficient synthesis of antihistamines clocinizine and chlorcyclizine. Med Chem Res 2011; 1-4
    PubMedGoogle Scholar