Download PDF
Arzneimittelforschung 2011; 61(1): 1-7
DOI: 10.1055/s-0031-1296161
CNS-active Drugs · Hypnotics · Psychotropics · Sedatives
Editio Cantor Verlag Aulendorf (Germany)

Synthesis of novel 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone derivatives and acetylcholinesterase and butyrylcholinesterase inhibitory activities in vitro

Semra Utku
1   Mersin University, Faculty of Pharmacy, Mersin, Turkey
,
Mehtap Gökçe
2   Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Beşevler, Ankara, Turkey
,
İlkay Orhan
3   Gazi University, Faculty of Pharmacy, Department of Pharmacognosy, Beşevler, Ankara, Turkey
,
M Fethi Şahin
2   Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Beşevler, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
28 November 2011 (online)

    Permissions and Reprints

Abstract

In this study thirteen 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(substituted/-nonsubstituted benzal)hydrazone V derivatives were synthesized as acetylcholinesterase and butyrylcholinesterase inhibitors. Ten of the synthesized compounds were synthesized for the first time in this study and the rest of them had been synthesized in a previous study. The structures of compounds V were elucidated by IR, 1H-NMR and MASS spectra. The acetylcholinesterase (AChE) and butyrylcholinesterase (BChe) inhibitory activities of V derivatives were measured using Ellman's method. While some of the 6-substituted-3(2H)-pyridazinone-2-propyl-3-(substituted/-nonsubstituted benzal)hydrazone V derivatives exhibited significant AChE inhibitory activity, none of the compounds showed BChE inhibitory activity. These results indicate that V derivatives were AChE inhibitors with AChE/BChE selectivity.

Key words

Acetylcholinesterase inhibitors - Benzal hydrazone - Butyrylcholinesterase inhibitors - 3(2H)-Pyridazinone
 

  • References

  • 1 Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD et al. Biological markers for therapeutic trials in Alzheimer's disease: Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Neurobiol Aging. 2003; 24: 521-36
    CrossrefPubMedGoogle Scholar
  • 2 Mosconi L, Brys M, Glodzik-Sobanska L, De Santi S, Rusinek H, de Leon MJ. Early detection of Alzheimer's disease using neuroimaging. Exp Gerontol. 2007; 42: 129-38
    CrossrefPubMedGoogle Scholar
  • 3 Beard CM, Kokmen E, Sigler C, Smith GE, Petterson T, O'Brien PC. Cause of death in Alzheimer's disease. Ann Epidemiol. 1996; 6: 195-200
    CrossrefPubMedGoogle Scholar
  • 4 Sadashiva CT, Chandra JN, Ponnappa KC, Veerabasappa T. Synthesis and efficacy of 1-bis(4-fluorophenyl)-methyl]pi-perazine derivatives for acetylcholineesterase inhibition, as a stimulant of central cholinergic neurotransmission in Alzheimer's disease. Bioorg Med Chem Lett. 2006; 16: 3932-6
    CrossrefPubMedGoogle Scholar
  • 5 Pakaski M, Kalman J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer's disease. Neu-rochem lnt. 2008; 53: 103-11
    PubMedGoogle Scholar
  • 6 Auld DS, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer's disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol. 2002; 68: 209-45
    CrossrefPubMedGoogle Scholar
  • 7 Ingram DK, Spangler EL, Iijima S, Ikari H, Kuo H, Greig NH et al. Rodent models of memory dysfunction in Alzheimer's disease and normal aging: Moving beyond the cholinergic hypothesis. Life Sci. 1994; 55: 2037-49
    CrossrefPubMedGoogle Scholar
  • 8 Masterman D. Cholinesterase inhibitors in the treatment of Alzheimer's disease and related dementias. Clin Geriat Med. 2004; 20: 59-68
    PubMedGoogle Scholar
  • 9 Zhang N, Casida JE. Novel irreversible butyrylcholinester-ase inhibitors: 2-chloro-1-(substituted phenyl)ethylpho-sphonic Acids. Bioorg Med Chem. 2002; 10 (05) 1281-90
    CrossrefPubMedGoogle Scholar
  • 10 Reale M, Iarlori C, Gambi F, Feliciani C, Isabella L, Gambi D. The acetylcholinesterase inhibitor, Donepezil, regulates a Th2 bias in Alzheimer's disease patients. Neuropharma-col. 2006; 50: 606-13
    CrossrefPubMedGoogle Scholar
  • 11 Shen Q, Peng Q, Shao J, Liu X, Huang Z, Pu X et al. Synthesis and biological evaluation of functionalized coumarins as acetylcholinesterase inhibitors. Eur J Med Chem. 2005; 40: 1307-15
    CrossrefPubMedGoogle Scholar
  • 12 X. Zhou, X. Wang, T. Wangb, L. Kong. Design, synthesis, and acetylcholinesterase inhibitory activity of novel cou-marin analogues. Bioorg Med Chem. 2008; 16: 8011-21
    CrossrefPubMedGoogle Scholar
  • 13 Boissier JR, Ratouis R, Dumont C. Synthesis and Pharmacological Study of New Piperazine Derivatives. Benzylpi-perazines. J Med Chem. 1963; 6 (05) 541-4
    CrossrefPubMedGoogle Scholar
  • 14 Elvio B, Parravicini F, Emilio T. Hydrazino pyridazines containing basic groups in the 6-position and possessing hypotensive activity. Farmaco Ed Sci. 1969; 24 (11) 919-29
    PubMedGoogle Scholar
  • 15 Gökçe M, Doğruer D, Şahin MF. Synthesis and antinociceptive activity of 6-substituted-3(2H)-pyridazinone derivatives. Farmaco. 2001; 56: 221-4
    PubMedGoogle Scholar
  • 16 Gökçe M, Şahin MF, Küpeli E, Yeşjilada E. Synthesis and analgesic and anti-inflammatory activity of new 3(2h)-pyrida-zinone derivatives. Arzneimittelforschung. 2004; 54: 396-401
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Şahin MF, Badιçoğlu B, Gökçe M, Küpeli E, Yeşilada E. Synthesis and analgesic and antiinflammatory activity of methyl [6-substitue-3(2H)-piridazinone-2-yl]acetate derivatives. Arch Pharm Med Chem. 2004; 337: 445-52
    CrossrefPubMedGoogle Scholar
  • 18 Gökçe M, Bakιr G, Şahin MF, Küpeli E, Yeşjlada E. synthesis of new Mannich bases of arylpyridazinones as analgesic and anti-inflammatory agents. Arzneimittelforschung. 2005; 55: 318-25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Dündar Y, Gökçe M, Küpeli E, Şahin MF. Synthesis and analgesic and antiinflammatory activity of ethyl 6-substi-tuted-3(2H)-pyridazinone-2-ylacetate derivatives. Arzneimittelforschung. 2007; 57: 777-81
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Özçelik AB, Gökçe M, Orhan I, Kaynak F, Şahin MF. Synthesis and antimicrobial, acetylcholinesterase and butyryl-cholinesterase inhibitory activities of novel ester and hy-drazide derivatives of 3(2H)-pyridazinone. Arzneimittelforschung. 2010; 60: 452-8
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Ellman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetricdetermination of acetylcholinesterase activity. Biochem Pharm. 1961; 7: 88-95
    CrossrefPubMedGoogle Scholar
  • 22 Orhan I, Aslan S, Kartal M, Şener B, Başer KHC. Inhibitory effect of Turkish Rosmarinus officinalis L. on acetylcholinesterase and butyrylcholinesterase enzymes. Food Chem. 2008; 108: 663-8
    CrossrefPubMedGoogle Scholar
  • 23 Gökçe M, Utku S, Küpeli E. Synthesis and analgesic and anti-inflammatory activities 6-substituted-3(2H)-pyridazi-none-2-acetyl-2-(p-substituted/nonsubstituted benzal)hy-drazone derivatives. Eur J Med Chem. 2009; 44: 3760-4
    CrossrefPubMedGoogle Scholar