IN-VITRO EVALUATION AND MOLECULAR DOCKING STUDIES OF SOME SCHIFF BASES AS CHOLINESTERASE INHIBITOR
Abstract
Some new Schiff bases of 4-aminopyridine were synthesized and evaluated for antiamnesic and cognition enhancing activity. In the current study to further understand the mechanism of action of these derivatives we have evaluated in-vitro acetycholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Enzyme kinetics and docking studies were performed for all compounds to observe their nature of inhibition. The IC50 value of synthesized compounds showed maximum activity of compound 4APg compared to standard drug donepezil and rivastigmine whereas its kinetic analysis of enzyme inhibition demonstrated non-competitive inhibition for both enzymes AChE and BChE. The docking study confirmed their consensual interaction with AChE and BChE active sites justifying the experimental outcome.
Keywords:
4-Aminopyridine, Antiacetycholinesterase, Antibutyrylcholinesterase, Enzyme kineticsDOI
https://doi.org/10.25004/IJPSDR.2015.070508References
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20. Lineweaver H, Burk DJ. The determination of enzyme dissociation constants. Am Chem Soc. 1934; 56: 658-666.
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2. World Alzheimer Report 2012, Overcoming the Stigma of Dementia. http://www.alz.co.uk/research/world-report-2012
3. Lahiri DK, Farlow MR, Greig NH, Sambamurti K. Current drug targets for Alzheimer’s disease treatment. Drug Dev Res. 2002; 56: 267–281.
4. Ghosh AK, Pandey S, Gangarajula S, Kulkarni S, Xu X, Rao KV, Huang X, Tang J. Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors. Bioorg Med Chem Lett. 2012; 22: 5460-5465.
5. Gundersen E, Fan K, Haas K, Huryn D, Steven JJ, Kreft A, Martone R, Mayer S, Sonnenberg RJ, Sun SC, Zhou H. Molecular-modeling based design, synthesis, and activity of substituted piperidines as gamma-secretase inhibitors. Bioorg Med Chem Lett. 2005; 15: 1891-1894.
6. Bartolini M, Bertucci C, Cavrini V, Andrisano V. beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. Biochem Pharmacol. 2003; 65: 407-416.
7. Giacobini E. Cholinesterases: new roles in brain function and in Alzheimer's disease. Neurochem Res. 2003; 28: 515‒522.
8. Combarros O, Riancho JA, Infante J, Sanudo C, Llorca J, Zarrabeitia MT, Berciano J. Interaction between CYP19 aromatase and butyrylcholinesterase genes increases Alzheimer's disease risk. Dement. Geriatr Cogn Disord. 2005; 20: 153-157.
9. Barak D, Kronman C, Ordentlich A, Naomi A, Bromberg A, Marcus D, Lazar A, Velan B, Shafferman A. () Acetylcholinesterase peripheral anionic site degeneracy conferred by amino acid arrays sharing a common core. J Biol Chem. 1994; 269: 6296-305.
10. Andersson CD, Forsgren N, Akfur C, Allgardsson A, Berg L, Engdahl C, Qian W, Ekstrom F, Linusson. A Divergent structure-activity relationship of structurally similar acetylcholinesterase inhibitors. J Med Chem. 2013; 56: 7615-7624.
11. Scipione L, De VD, Musella A, Flammini L, Bertoni S, Barocelli E. 4-Aminopyridine derivatives with anticholinesterase and antiamnesic activity. Bioorg Med Chem Lett. 2008; 18: 309-312.
12. Cavallito CJ, Yun HS, Edwards ML, Foldes FF. Choline acetyltransferase inhibitors. Styrylpyridine analogs with nitrogen-atom modifications. J Med Chem. 1971; 14: 130-133.
13. Andreani A, Leoni A, Locatelli A, Morigi R, Rambaldi M, Pietra C, Villetti G. 4-Aminopyridine derivatives with antiamnesic activity. Eur J Med Chem. 2000; 35: 77-82.
14. Alptuzun V, Prinz M, Horr V, Scheiber J, Radacki K, Fallarero A, Vuorela P, Engels B, Braunschweig H, Erciyas E, Holzgrabe U. Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with beta-amyloid, acetylcholine, and butyrylcholine esterases. Bioorg Med Chem. 2010; 18: 2049-2059.
15. Campagna F, Catto M, Purgatorio R, Altomare CD, Carotti A, De Stradis A, Palazzo G. Synthesis and biophysical evaluation of arylhydrazono-1H-2-indolinones as β-amyloid aggregation inhibitors. Eur J Med Chem. 2011; 46: 275-284.
16. Huang L, Luo Z, He F, Lu J, Li X. Synthesis and biological evaluation of a new series of berberine derivatives as dual inhibitors of acetylcholinesterase and butyrylcholinesterase. Bioorg Med Chem. 2010; 18: 4475-4484.
17. Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961; 7: 88-95.
18. Sinha SK, Shrivastava SK. Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents. Bioorg Med Chem. 2013; 21: 5451-5460.
19. Sinha SK, Shrivastava SK. Design, synthesis and evaluation of some new 4-amino pyridine derivatives in learning and memory. Bioorg Med Chem Lett. 2013; 23: 2984-2989.
20. Lineweaver H, Burk DJ. The determination of enzyme dissociation constants. Am Chem Soc. 1934; 56: 658-666.
21. Darvesh S, Hopkins DA, Geula C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci. 2003; 4: 131-138.
22. Mesulam MM, Guillozet A, Shaw P, Levey A, Duysen EG, Lockridge O. Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience. 2002; 110: 627-639.
Published
01-09-2015
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“IN-VITRO EVALUATION AND MOLECULAR DOCKING STUDIES OF SOME SCHIFF BASES AS CHOLINESTERASE INHIBITOR”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 7, no. 5, Sept. 2015, pp. 421-42, https://doi.org/10.25004/IJPSDR.2015.070508.
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How to Cite
“IN-VITRO EVALUATION AND MOLECULAR DOCKING STUDIES OF SOME SCHIFF BASES AS CHOLINESTERASE INHIBITOR”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 7, no. 5, Sept. 2015, pp. 421-42, https://doi.org/10.25004/IJPSDR.2015.070508.
