Login Register Cart 0
Generic placeholder image

Anti-Infective Agents

Editor-in-Chief

ISSN (Print): 2211-3525
ISSN (Online): 2211-3533

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis of piperidine-4-one Derivative Containing Dipeptide: An Acetyl cholinesterase and β-secretase Inhibitor

Author(s): Parasuraman Pavadai*, Suresh Ramalingam, Theivendren Panneerselvam, Selvaraj Kunjiappan, Pandurangan Perumal, Vasudevan Mani, Govindaraj Saravanan, Veerachamy Alagarsamy, Damodar Nayak Ammunje and Jithendra Chimakurthy

Volume 18, Issue 2, 2020

Page: [160 - 168] Pages: 9

DOI: 10.2174/2211352517666190405155505

Abstract

Background: With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized novel piperidone fused dipeptide (DPPS) derivatives possessing dual action such as acetylcholinesterase (AChE) and beta-amyloid peptide (Aβ) aggregation inhibition. Designed peptide was synthesized by solid phase peptide synthesis using FMOC chemistry protocol and characterized by mass spectroscopy.

Methods: The amino acid sequence in peptide was analyzed by LC-MS-MS. In silico docking analysis was carried out using GLIDE software. The docking score using GLIDE was found to be -7.88 against AChE and -9.74 against BACE1 enzyme. In vitro enzyme inhibition assay was carried out for AChE enzyme and BACE1 enzyme.

Results: The IC50 values of AChE inhibition and BACE1 of DPPS were found to be 0.4796 μM/ml and 0.0154 μM/ml, respectively. The correlation of in silico and in vitro results showed that DPPS possessed a greater ability to inhibit BACE1 enzyme.

Keywords: Alzheimers disease, peptides, DPPS, enzyme inhibition, AChE, BACE1.

Graphical Abstract

[1]
Ghosh, A.K.; Kumaragurubaran, N.; Tang, J. Recent developments of structure based β-secretase inhibitors for Alzheimer’s disease. Curr. Top. Med. Chem., 2005, 5(16), 1609-1622.
[http://dx.doi.org/10.2174/156802605775009711] [PMID: 16375745]
[2]
Guo, T.; Hobbs, D.W. Development of BACE1 inhibitors for Alzheimer’s disease. Curr. Med. Chem., 2006, 13(15), 1811-1829.
[http://dx.doi.org/10.2174/092986706777452489] [PMID: 16787223]
[3]
Morphy, R.; Rankovic, Z. Designing multiple ligands - medicinal chemistry strategies and challenges. Curr. Pharm. Des., 2009, 15(6), 587-600.
[http://dx.doi.org/10.2174/138161209787315594] [PMID: 19199984]
[4]
Bolognesi, M.L.; Cavalli, A.; Valgimigli, L.; Bartolini, M.; Rosini, M.; Andrisano, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed drug design strategy: from a dual binding site acetylcholinesterase inhibitor to a trifunctional compound against Alzheimer’s disease. J. Med. Chem., 2007, 50(26), 6446-6449.
[http://dx.doi.org/10.1021/jm701225u] [PMID: 18047264]
[5]
Marco-Contelles, J.; León, R.; de los Ríos, C.; Samadi, A.; Bartolini, M.; Andrisano, V.; Huertas, O.; Barril, X.; Luque, F.J.; Rodríguez-Franco, M.I.; López, B.; López, M.G.; García, A.G.; Carreiras, Mdo.C.; Villarroya, M. Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer’s disease. J. Med. Chem., 2009, 52(9), 2724-2732.
[http://dx.doi.org/10.1021/jm801292b] [PMID: 19374444]
[6]
John, V.; Beck, J.P.; Bienkowski, M.J.; Sinha, S.; Heinrikson, R.L. Human beta-secretase (BACE) and BACE inhibitors. J. Med. Chem., 2003, 46(22), 4625-4630.
[http://dx.doi.org/10.1021/jm030247h] [PMID: 14561080]
[7]
Kornilova, A.Y.; Wolfe, M.S. Secretase inhibitors for Alzheimer’s disease. Annu. Rep. Med. Chem., 2003, 38, 41-50.
[http://dx.doi.org/10.1016/S0065-7743(03)38006-6]
[8]
Pákáski, M.; Kálmán, J. Interactions between the amyloid and cholinergic mechanisms in Alzheimer’s disease. Neurochem. Int., 2008, 53(5), 103-111.
[http://dx.doi.org/10.1016/j.neuint.2008.06.005] [PMID: 18602955]
[9]
Lien, S.; Lowman, H.B. Therapeutic peptides. Trends Biotechnol., 2003, 21(12), 556-562.
[http://dx.doi.org/10.1016/j.tibtech.2003.10.005] [PMID: 14624865]
[10]
Parasuraman, P.; Suresh, R.; Premnath, D. Balancing anti-amyloid and anti-cholinesterase capacity in a single chemical entity: In silico drug design. Int. J. Pharm. Pharm. Sci., 2014, 6(2), 571-572.
[11]
Choi, H.; Aldrich, J.V. Comparison of methods for the Fmoc solid-phase synthesis and cleavage of a peptide containing both tryptophan and arginine. Int. J. Pept. Protein Res., 1993, 42(1), 58-63.
[http://dx.doi.org/10.1111/j.1399-3011.1993.tb00350.x] [PMID: 8103765]
[12]
Fields, C.G.; Fields, G.B. Solvents for solid-phase peptide synthesis. Methods Mol. Biol., 1994, 35, 29-40.
[PMID: 7894606]
[13]
Fields, C.G.; Lloyd, D.H.; Macdonald, R.L.; Otteson, K.M.; Noble, R.L. HBTU activation for automated Fmoc solid-phase peptide synthesis. Pept. Res., 1991, 4(2), 95-101.
[http://dx.doi.org/10.1007/978-94-011-3034-9_23] [PMID: 1815783]
[14]
Chan, W.C.; White, P.D. FMOC solid phase peptide synthesis: A practical approach;, Hames, B.D., Ed.; 41
[15]
Ellman, G.L.; Courtney, K.D.; Andres, V., Jr; Feather-Stone, R.M. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol., 1961, 7, 88-95.
[http://dx.doi.org/10.1016/0006-2952(61)90145-9] [PMID: 13726518]
[16]
Rees, T.M.; Brimijoin, S. The role of acetylcholinesterase in the pathogenesis of Alzheimer’s disease. Drugs Today (Barc), 2003, 39(1), 75-83.
[http://dx.doi.org/10.1358/dot.2003.39.1.740206] [PMID: 12669110]

Rights & Permissions Print Cite
Article Metrics
16
1
© 2024 Bentham Science Publishers | Privacy Policy