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Arzneimittelforschung 2012; 62(12): 655-660
DOI: 10.1055/s-0032-1329963
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Synthesis, Biological Activity and Molecular Modeling of 4-Fluoro-N-[ω-(1,2,3,4-tetrahydroacridin-9-ylamino)-alkyl]-benzamide Derivatives as Cholinesterase Inhibitors

P. Szymański
1   Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
,
M. Markowicz
1   Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
,
M. Bajda
2   Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
,
B. Malawska
2   Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
,
E. Mikiciuk-Olasik
1   Department of Pharmaceutical Chemistry and Drug Analyses, Medical University, Lodz, Poland
› Author Affiliations
Further Information

Publication History

received 27 July 2012

accepted 21 October 2012

Publication Date:
15 November 2012 (online)

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Abstract

The aim of this study was to synthesize and determine the biological activity of new deri­vatives of 4-fluorobenzoic acid and tetrahydroacridine towards inhibition of cholinesterases. Compounds were synthesized in condensation reaction between 9-aminoalkyl-tetrahydroacri­dines and the activated 4-fluorobenzoic acid. Properties towards inhibition of acetyl- and butyrylcholinesterase were estimated according to Ellman’s spectrophotometric method. Among synthesized compounds the most active were compounds 4a and 4d. These compounds, in comparison with tacrine, were characterized by the similar values of IC50. Among all obtained compounds, 4d presented the highest selectivity towards inhibition of acetylcholinesterase. Molecular modeling studies revealed that all derivatives presented similar extended conformation in the gorge of acetylcholinesterase, however, there were 2 main conformations in the active center of butyrylcholinesterase: bent and extended conformation.

Key words

Alzheimer’s disease - tacrine - fluorobenzoic acid - docking - Ellman’s method

Literatur

 

  • References

  • 1 Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet 2006; 368: 387-403
    CrossrefPubMedGoogle Scholar
  • 2 Weiner MW, Aisen PS, Jack CR et al. The Alzheimer’s disease neuroimaging initiative: progress report and future plans. Alzheimer Dement 2010; 6: 202-211
    CrossrefPubMedGoogle Scholar
  • 3 Mucke L. Neuroscience: Alzheimer’s disease. Nature 2009; 461: 895-897
    CrossrefPubMedGoogle Scholar
  • 4 Petrella JR, Coleman E, Doraiswamy PM. Neuroimaging and Early Diagnosis of Alzheimer Disease. Radiology 2003; 226: 315-336
    CrossrefPubMedGoogle Scholar
  • 5 Greig NH, Utsuki T, Ingram DK et al. Selective butyrylcholinesterase inhibition elevates brain acetylcholine, augments learning and lowers Alzheimer -amyloid peptide in rodent. P Natl Acad Sci 2005; 102 (47) 17213-17218
    CrossrefPubMedGoogle Scholar
  • 6 Ryu EK, Choe YS, Park EY et al. Synthesis and evaluation of 2-[18F]fluoro-CP-118,954 for the in vivo mapping of acetylcholinesterase. Nucl Med Biol 2005; 32: 185-191
    CrossrefPubMedGoogle Scholar
  • 7 Tavitian B, Pappata S, Bonnot-Lours S et al. Positron emission tomography study of [11C]methyl-tetrahydroaminoacridine (methyl-tacrine) in baboon brain. Eur J Pharmacol 1993; 236: 229-238
    CrossrefPubMedGoogle Scholar
  • 8 Pappata S, Tavitian B, Traykov L et al. In Vivo Imaging of Human Cerebral Acetylcholinesterase. J Neurochem 1996; 67: 876-879
    PubMedGoogle Scholar
  • 9 Lee S-Y, Choe YS, Sugimoto H et al. Synthesis and biological evaluation of 1-(4-[18F]fluorobenzyl)-4- [(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine for in vivo studies of acetylcholinesterase. Nucl Med Biol 2000; 27: 741-744
    CrossrefPubMedGoogle Scholar
  • 10 Choe YS, Oh SJ, Shim I et al. Syntheses and biological evaluation of 18F-labeled 3-(1-benzylpiperidin-4-yl)-1-(1-methyl-1H-indol-3-yl)propan-1-ones for in vivo mappingof acetylcholinesterase. Nucl Med Biol 2000; 27: 263-267
    CrossrefPubMedGoogle Scholar
  • 11 Liston DR, Nielsen JA, Villalobos A et al. Pharmacology of selective acetylcholinesterase inhibitors: Implications for use in Alzheimer’s disease. Eur J Pharmacol 2004; 486: 9-17
    CrossrefPubMedGoogle Scholar
  • 12 Pakaski M, Kalman J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer’s disease. Neurochem Int 2008; 53: 103-111
    CrossrefPubMedGoogle Scholar
  • 13 Sabbagh NM, Richardson S, Relkin N. Disease-modifying approaches to Alzheimer’s disease: Challenges and opportunities-lessons from donepezil therapy. Alzheimer Dement 2008; 4: 109-118
    PubMedGoogle Scholar
  • 14 Hagmann WK. The Effect of Fluorine Substitution on. pKa. J Med Chem 2008; 51: 4359-4369
    CrossrefPubMedGoogle Scholar
  • 15 Hu M-K, Wu L-J, Hsiao G et al. Homodimeric Tacrine Congeners as Acetylcholinesterase Inhibitors. J Med Chem 2002; 11: 2277-2282
    PubMedGoogle Scholar
  • 16 Szymański P, Karpiński A, Mikiciuk-Olasik E. Synthesis, biological activity and HPLC validation of 1,2,3,4-tetrahydroacridine derivatives as acetylcholinesterase inhibitors. Eur J Med Chem 2011; 46: 3250-3257
    CrossrefPubMedGoogle Scholar
  • 17 Carlier PR, Du DM, Han Y et al. Potent, Easily Synthesized Huperzine A-Tacrine Hybrid Acetylcholinesterase Inhibitors. Bioorg Med Chem Lett Aug 1999; 9 (16) 2335-2338
    CrossrefPubMedGoogle Scholar
  • 18 Szymanski P, Markowicz M, Mikiciuk-Olasik E. Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors. Bioorg Chem 2011; 39 (04) 138-142
    CrossrefPubMedGoogle Scholar
  • 19 Dorronsoro I, Alonso D, Castro A et al. Synthesis and Biological Evaluation of Tacrine-Thiadiazolidinone Hybrids as Dual Acetylcholinesterase Inhibitors. Arch Pharm Chem Life Sci 2005; 338: 18-23
    CrossrefPubMedGoogle Scholar
  • 20 Carlier PR, Han YF, Chow ES-W et al. Evaluation of short-tether Bis-THA AChE inhibitors. A further test of the dual binding site hypothesis. Bioorg Med Chem 1999; 7: 351-357
    CrossrefPubMedGoogle Scholar
  • 21 Rosini M, Andrisano V, Bartolini M et al. Rational Approach to discover multipotent anti-Alzheimer drugs. J Med Chem 2005; 48: 360-363
    CrossrefPubMedGoogle Scholar
  • 22 Fang L, Kraus B, Lehmann J et al. Tacrine–ferulic Acid Hybrids as Multi-potent Anti-Alzheimer Drug Candidates. Bioorg Med Chem 2008; 18: 2905-2909
    CrossrefPubMedGoogle Scholar
  • 23 Carlier PR, Chow ES-W, Han YF et al. Heterodimeric Tacrine-Based Acetylcholinesterase Inhibitors: Investigating Ligand − Peripheral Site Interactions. J Med Chem 1999; 42: 4225-4231
    CrossrefPubMedGoogle Scholar
  • 24 Fang L, Appenroth D, Decker M et al. Tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity. J Med Chem 2008; 51: 7666-7669
    CrossrefPubMedGoogle Scholar
  • 25 Kamiński ZJ. 2-Chloro-4,6-dimethoxy-1,3,5-triazine. A New Coupling Reagent for Peptide Synthesis. Synthesis 1987; 917-920
    Article in Thieme ConnectPubMedGoogle Scholar
  • 26 Blotny G. Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis. Tetrahedron 2006; 62: 9507-9522
    CrossrefPubMedGoogle Scholar
  • 27 Ellman GL, Courtney KD, Andres V et al. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharm 1961; 7: 88-95
    CrossrefPubMedGoogle Scholar
  • 28 Cheng YC, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharm 1973; 22: 3099-3108
    CrossrefPubMedGoogle Scholar
  • 29 Tipton KF. Commentary: Enzyme kinetics in relation to enzyme inhibitors. Biochem Pharm 1973; 22: 2933-2941
    CrossrefPubMedGoogle Scholar
  • 30 Szymański P, Markowicz M, Bajda M et al. Synthesis and biological activity of new 2,3-dihydro-1H-cyclopenta[b]quinoline derivatives as acetylcholinesterase inhibitors. Lett Drug Des Discov 2012; 9: 645-654
    CrossrefPubMedGoogle Scholar