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Arzneimittelforschung 2010; 60(7): 452-458
DOI: 10.1055/s-0031-1296311
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Synthesis and antimicrobial, acetylcholinesterase and butyrylcholinesterase inhibitory activities of novel ester and hydrazide derivatives of 3 (2H)-pyridazinone

Azime Berna Ozçelik
1   Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Besevler, Ankara, Turkey
,
Mehtap Gokçe
1   Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Besevler, Ankara, Turkey
,
Ilkay Orhan
2   Gazi University, Faculty of Pharmacy, Department of Pharmacognosy, Besevler, Ankara, Turkey
,
Fatma Kaynak
3   Gazi University, Faculty of Pharmacy, Department of Microbiology, Besevler, Ankara, Turkey
,
Mustafa Fethi Şahin
1   Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Besevler, Ankara, Turkey
› Author Affiliations
Further Information

Publication History

Publication Date:
03 December 2011 (online)

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Abstract

In the current study, some novel ethyl 6-[(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionate III and 6-[(substituted-phenylpiperazine]-3(2H)-pyridazinone-2-yl propionohydrazide IV derivatives were synthesized as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The structures of these new pyridazinone derivatives were confirmed by their IR, 1H-NMR spectra and elementary analysis. 6-Sub-stituted-3(2H)-pyridazinone-2-yl propionate IIIa-e derivatives showed significant inhibitory activity against AChE and BChE. 6- [4- (3-Trifluoromethylphenyl) -piperazine] -3 (2H) -pyridazinone-2-yl propionate IIIe has been found to be the most active compound in terms of inhibition of either AChE or BChE. Compound IIIe exhibited inhibitory activity close to that of galantamine (CAS 357-70-0) and did not show any selectivity between the two enzymes. Also the antimicrobial activities of III and IV derivatives have been evaluated. All III and IV derivatives exhibited poor antibacterial activities but moderate antifungal activities.

Key words

Acetylcholinesterase inhibitors - Antimicrobial activity - Butyrylcholinesterase inhibitors - 3(2H)-Pyridazinone-2-yl esters - 3(2H)-Pyridazinone-2-yl hydrazides
 

  • References

  • 1 Loncle C, Brunei JM, Vidal N, Dherbomez M, Letourneux Y. Synthesis and antifungal activity of cholesterol-hydrazone derivatives. Eur J Med Chem. 2004; 39: 1067-71
    CrossrefPubMedGoogle Scholar
  • 2 Kücükgüzel SG, Mazi A, Sahin F, Öztürk S, Stables J. Synthesis and biological activities of diflunisal hydrazide-hydrazones. Eur J Med Chem. 2003; 38: 1005-13
    CrossrefPubMedGoogle Scholar
  • 3 Todeschini AR, Miranda ALP, Silva KCM, Parrini SC, Barreiro EJ. Synthesis and evaluation of analgesic, antiinflammatory and antiplatelet properties of new 2-pyridylaryl-hydrazone derivatives. Eur J Med Chem. 1998; 33: 189-99
    CrossrefPubMedGoogle Scholar
  • 4 Melnyk P, Leroux V, Sergheraert C, Greffier P. Design, synthesis and in vitro antimalarial activity of an acylhydra-zone library. Bioorg Med Chem Lett. 2006; 16: 31-5
    CrossrefPubMedGoogle Scholar
  • 5 Leite LFCC, Ramos MN, da BPSilva, Miranda ALP, Fraga CAM, Barreiro EJ. Synthesis, anti-inflammatory and antimicrobial activities of new 1,2,4-oxadiazoles peptidomimetics. Farmaco. 1999; 54: 747-57
    CrossrefPubMedGoogle Scholar
  • 6 Lima PC, Lima L, da MSilva, Léda PHO, Miranda ALP, Fraga CAM et al Synthesis and analgesic activity of novel IV-acylarylhydrazones and is osters, derived from natural safrole. Eur J Med Chem. 2000; 35: 187-203
    CrossrefPubMedGoogle Scholar
  • 7 Cunha AC, Figueiredo JM, Tributino JLM, Miranda ALP, Castro HC, Zingali RB et al Antiplatelet properties of novel IV-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives. Bioorg Med Chem. 2003; 11: 2051-9
    CrossrefPubMedGoogle Scholar
  • 8 Koçyigit B, Oruç E, Unsalan S, Kandemirli F, Shvets N, Rollas S et al Synthesis and characterization of novel hydrazide-hydrazones and the study of their structure-antituberculosis activity. Eur J Med Chem. 2006; 41: 1253-61
    CrossrefPubMedGoogle Scholar
  • 9 Terzioglu N, Gürsoy A. Synthesis and primary cytotoxicity evaluation of 3-[[(3-phenyl-4(3H)-quinazolinone-2-yl)mer-captoacetyl]hydrazono]-1H-2-indolinones. Eur J Med Chem. 2003; 38: 781-6
    CrossrefPubMedGoogle Scholar
  • 10 Galic N, Peric B, Kojic-Prodic B, Cimerman Z. Structural and spectroscopic characteristics of aroylhydrazones derived from nicotinic acid hydrazide. J Mol Struc. 2001; 559: 187-94
    CrossrefPubMedGoogle Scholar
  • 11 Kaynak FB, Öztürk D, Özbey S, Çapan G. New N-alkylidene/cycloalkylidene derivatives of 5-methyl-3-phenyl-1H-indole-2-carbohydrazide: synthesis, crystal structure, and quantum mechanical calculations. Mol Struc. 2005; 740: 213-21
    PubMedGoogle Scholar
  • 12 Rostom SA, Shalaby MA, El-Demellawy MA. Polysubstituted pyrazoles, part 5. Synthesis of new 1-(4-chlorophe-nyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs and some derived ring systems: a novel class of potential antitumor and anti-HCV agents. Eur J Med Chem. 2003; 38: 959-74
    CrossrefPubMedGoogle Scholar
  • 13 Bernardino AMR, Gomes AO, Charret KS, Freitas ACC, Machado GMC, Canto-Cavalheiro MM et al Synthesis and leishmanicidal activities of 1-(4-X-phenyl)-N’-[(4-Y-phe-nyl)methylene]-1H-pyrazole-4-carbohydrazides. Eur J Med Chem. 2006; 41: 80-7
    CrossrefPubMedGoogle Scholar
  • 14 Dal Piaz V, Giovannoni MP, Ciciani G, Becherucci C, Parente L. 4-Substituted-5-acetyl-2-methyl-6-phenyl 3(2H)py-ridazinones as PGE2 and IL-1 release inhibitors from mouse adherent macrophages. Pharm Res. 1994; 29: 367-72
    CrossrefPubMedGoogle Scholar
  • 15 Franzen K, Saveman B, Blomqvist K. Predictors for health related quality of life in persons 65 years or older with chronic heart failure. Eur J Card Nurs. 2007; 6: 112-20
    PubMedGoogle Scholar
  • 16 Nieminen MS, Cleland JGF, Eha J, Belenkov Y, Kivikko M, Poder P et al Oral levosimendan in patients with severe chronic heart failure: the PERSIST study. Eur J Heart Fail. 2008; 10: 1246-54
    CrossrefPubMedGoogle Scholar
  • 17 Sotelo E, Fraiz N, Yanez M, Terrades V, Laguna R. , Cano E. Pyridazines. Part XXIX. Synthesis and platelet aggregation inhibition activity of 5-substituted-6-phenyl-3(2H)-pyridazinones: novel aspects of their biological actions. Bioorg Med Chem. 2002; 10: 2873-82
    CrossrefPubMedGoogle Scholar
  • 18 Schudt C, Winder S, Müller B, Ukena D. Zardaverine as a selective inhibitor of phosphodiesterase isozymes. Biochem Pharm. 1991; 42: 153-62
    CrossrefPubMedGoogle Scholar
  • 19 Sudo T, Tachibana K, Toga K, Tochizawa S, Inoue Y, Kimura Y et al Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem. Pharmacol. 2000; 59 (4) 347-56
    CrossrefPubMedGoogle Scholar
  • 20 Roma G, Di MBraccio, Grossi G, Piras D, Leoncini G, Bruzzese D et al Synthesis and in vitro antiplatelet activity of new 4-(l-piperazinyl)coumarin derivatives: human platelet phosphodiesterase 3 inhibitory properties of the two most effective compounds described and molecular modeling study on their interactions with phosphodiesterase 3A catalytic site. J Med Chem. 2007; 50 (12) 2886-95
    CrossrefPubMedGoogle Scholar
  • 21 Matsuo T, Tsukamoto Y, Takagi T, Sato M. Synthesis and biological activity of pyridazinooxazines. Chem Pharm Bull. 1982; 30 (3) 832-42
    CrossrefPubMedGoogle Scholar
  • 22 Takaya M, Sato M. Analgesic-anti-inflammatory activities of 3(2H\)-pyridazinone derivatives. Yakugaku Zasshi. 1994; 114 (2) 94-110
    PubMedGoogle Scholar
  • 23 Piaz D, Vergelli C, Giovannoni MP, Scheideler MA, Petrone G, Zaratin P. 4-Amino-3(2H)-pyridazinones bearing arylpiperazinylalkyl groups and related compounds: synthesis and antinociceptive activity. Farmaco. 2003; 58: 1063-71
    CrossrefPubMedGoogle Scholar
  • 24 Li CS, Brideau C, Chan CC, Savoie C, Claveau D, Charleson S et al Pyridazinones as selective cyclooxygenase-2 inhibitors. Bioorg Med Chem Lett. 2003; 13: 597-600
    CrossrefPubMedGoogle Scholar
  • 25 Chintakunta VK, Akella V, Vedula MS, Mamnoor PK, Mishra P, Casturi SR et al 3-O-substituted benzyl pyridazi-none derivatives as COX inhibitors. Eur J Med Chem. 2002; 37: 339-47
    CrossrefPubMedGoogle Scholar
  • 26 Dogruer DS, Çahin MF, Ünlü S, Ito S. Studies on some 3(2H)-pyridazinone derivatives with antinociceptive activity. Arch Pharm Med Chem. 2000; 333: 79-86
    CrossrefPubMedGoogle Scholar
  • 27 Piaz VD, Giovannoni MP, Ciciani G, Barlocco D, Giardina G, Petrone G et al 4,5-Functionalized 6-phenyl-3(2H)-pyridazinones: synthesis and evaluation of antinociceptive activity. Eur J Med Chem. 1996; 31: 65-70
    CrossrefPubMedGoogle Scholar
  • 28 Dal VPiaz, Vergelli C, Giovannoni MP, Scheider MA, Petrone G, Zaratin P. 4-Amino-3(2H)-pyridazinones bearing arylpiperazinylalkyl groups and related compounds: synthesis and antinociceptive activity. Farmaco. 1997; 58: 1063-71
    PubMedGoogle Scholar
  • 29 Sönmez M, Berber I, Akbas E. Synthesis, antibacterial and antifungal activity of some new pyridazinone metal complexes. Eur J Med Chem. 2006; 41: 101-5
    CrossrefPubMedGoogle Scholar
  • 30 Akbas E, Berber I, Sener A, Hasanov B. Synthesis and antibacterial activity of 4-benzoyl-l-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid and derivatives. Farmaco. 2005; 60: 23-6
    CrossrefPubMedGoogle Scholar
  • 31 Malinka W, Redzicka A, Lozach O. New derivatives of pyrrolo[3,4-d]pyridazinone and their anticancer effects. Farmaco. 2004; 59: 457-62
    CrossrefPubMedGoogle Scholar
  • 32 Cacabelos R, Alvarez A, Fenandez-Novoa L, Lombardi VR. A pharmacogenomic approach to Alzheimer’s disease. Acta Neurol Scand. 2000; 176: 12-9
    PubMedGoogle Scholar
  • 33 Jia P, Sheng R, Zhang J, Fang L, He Q, Yang B et al Design, synthesis and evaluation of galanthamine derivatives as acetylcholinesterase inhibitors. Eur J Med Chem. 2009; 44: 772-84
    CrossrefPubMedGoogle Scholar
  • 34 Alonso D, Dorronsoro I, Rubio L, Munoz E, Garcia-Palomero P, Del MMonte et al Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioor Med Chem. 2005; 13: 6588-97
    CrossrefPubMedGoogle Scholar
  • 35 Marcelo F, Silva FVM, Goulart M, Justino J, Sinay P, Blériot Y et al Synthesis of novel purine nucleosides towards a selective inhibition of human butyrylcholine-sterase. Bioorg Med Chem. 2009; 17: 5106-16
    CrossrefPubMedGoogle Scholar
  • 36 Gokçe M, Dogruer D, Sahin MF. Synthesis and antinociceptive activity of 6-substituted-3(2H)-pyridazinone derivatives. Farmaco. 2001; 56: 221-4
    PubMedGoogle Scholar
  • 37 Gokçe M, Sahin MF, Küpeli E, Yesilada E. Synthesis and evaluation of the analgesic and anti-inflammatory activity of new 3(2H) -pyridazinone derivatives. Arzneimittelforschung. 2004; 54 (7) 396-401
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Sahin MF, Badiçoglu B, Gokçe M, Küpeli E, Yeşilada E. Synthesis and analgesic and antiinflammatory activity of methyl [6-substituted-3(2H)-piridazinone-2-yl]acetate derivatives. Arch Pharm Med Chem. 2004; 337: 445-52
    CrossrefPubMedGoogle Scholar
  • 39 Gokçe M, Bakir G, Sahin MF, Küpeli E, Yesilada E. Synthesis of new Mannich bases of arylpyridazinones as analgesic and anti-inflammatory agents. Arzneimittelforschung. 2005; 55 (6) 318-25
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Dündar Y, Gokçe M, Küpeli E, Çahin MF. Synthesis and analgesic and anti-inflammatory activity of ethyl (6-substituted-3(2H)-pyridazinone-2-yl) acetate derivatives. Arzneimittelforschung. 2007; 57 (12) 777-81
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Gökce M, Çolak MS, Küpeli E, Sahin MF. Synthesis and analgesic and anti-inflammatory activity of 6-phenyl/(4-methylphenyl)-3(2H)-pyridazmon-2-propionamide derivatives. Arzneimittelforschung. 2009; 59 (7) 357-63
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Elman GL, Courtney KD, Andres V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharm. 1961; 7: 88-95
    CrossrefPubMedGoogle Scholar
  • 43 Orhan I, Asian S, Kartal M, Sener B, Baser KHC. Inhibitory effect of Turkish Rosmarinus officinalis L. on acetylcholinesterase and butyrylcholinesterase enzymes. Food Chem. 2008; 108: 663-8
    CrossrefPubMedGoogle Scholar
  • 44 Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS), Wayne, Pennsylvania, USA; 2008.
    PubMed
  • 45 Clinical and Laboratory Standards Institute (CLSI) (formerly NCCLS), Wayne, Pennsylvania, USA; 2006.
    PubMed
  • 46 Boissier JR, Ratouis R, Dumont C. Synthesis and pharmacological study of new piperazine derivatives: benzylpiper-azines. J Med Chem. 1963; 6 (5) 541-4
    CrossrefPubMedGoogle Scholar
  • 47 Elvio B, Parravicini F, Emilio T. Hydrazino pyridazines containing basic groups in the 6-position and possessing hypotensive activity. Farmaco Ed Sei. 1969; 24 (11) 919-29
    PubMedGoogle Scholar