Skip to content
2000
Volume 21, Issue 9
  • ISSN: 1573-4072
  • E-ISSN: 1875-6646

Abstract

Introduction

According to WHO, Alzheimer’s disease was estimated at 74.4 million cases in 2023, which will increase by 152.8 million cases in 2050. The therapeutic options available in the market for the treatment of AD are only capable of reducing the symptoms of dementia but not preventing progressive degeneration. Memantine is a non-competitive NMDAR antagonist used for the treatment of patients with moderate-to-severe AD, but it has a high toxicity profile. To counter this, the Memantine Schiff base derivatives were designed as simple and low-toxicity compounds.

Materials and Methods

Molecular docking was performed against the targeted enzymes Acetylcholinesterase and Butyrylcholinesterase using AUTODOCK 1.5.7 software. A series of novel Memantine derivatives of Schiff base were synthesized by condensing Memantine with various aryl aldehydes and screened for their -cholinesterase inhibitory activity towards Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) by Ellman’s method.

Results and Discussion

Among the designed compounds, compounds LMV and LMC showed maximum binding scores of -10.35 kcal/mol and -10.12 kcal/mol, respectively, than the standard Donepezil (-8.78 kcal/mol) against Acetylcholinesterase. The compounds LMONB and LMDMB produced significant binding scores of -9.31 kcal/mol and -9.11 kcal/mol, respectively, compared to the standard Donepezil (-7.57 kcal/mol) against Butyrylcholinesterase. Also, compounds LMV (30.9 ± 2.13 μM) and LMDMB (13.51 ± 1.12 μM) showed potent inhibitory activity against the AChE and BChE. These compounds possess drug-like characteristics and are also capable of crossing the Blood-brain Barrier (BBB).

Conclusion

The studied compounds LMV and LMDMB, being non-toxic, obey Lipinski’s rule of 5 and are potential inhibitors against targeted enzymes, which may be promising clinical candidates for treating Alzheimer’s disease.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cbc/10.2174/0115734072326297240919095545
2024-10-09
2025-10-22

  • From This Site

    /content/journals/cbc/10.2174/0115734072326297240919095545
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. BartoliniM. BertucciC. CavriniV. AndrisanoV. β-Amyloid aggregation induced by human acetylcholinesterase: Inhibition studies.Biochem. Pharmacol.200365340741610.1016/S0006‑2952(02)01514‑9 12527333
     [Google Scholar]
  2. DuX. WangX. GengM. Alzheimer’s disease hypothesis and related therapies.Transl. Neurodegener.201871210.1186/s40035‑018‑0107‑y 29423193
     [Google Scholar]
  3. GrahamW.V. Bonito-OlivaA. SakmarT.P. Update on Alzheimer’s disease therapy and prevention strategies.Annu. Rev. Med.201768141343010.1146/annurev‑med‑042915‑103753 28099083
     [Google Scholar]
  4. BallardC. GauthierS. CorbettA. BrayneC. AarslandD. JonesE. Alzheimer’s disease.Lancet201137797701019103110.1016/S0140‑6736(10)61349‑9 21371747
     [Google Scholar]
  5. OsmaniyeD. AhmadI. SağlıkB.N. LeventS. PatelH.M. OzkayY. KaplancıklıZ.A. Design, synthesis, and molecular docking and ADME studies of novel hydrazone derivatives for AChE inhibitory, BBB permeability and antioxidant effects.J. Biomol. Struct. Dyn.2022117 36325982
     [Google Scholar]
  6. Membrane charge dependent states of the beta-amyloid fragment Abeta (16-35) with differently charged micelle aggregates. 36325982
     [Google Scholar]
  7. KhanShoaib.; Ullah, Hayat.; Hussain, Rafaqat.; Khan, Yousaf.; Khan, Misbah Ullah.; Khan, Mehmand.; Sattar, Abdul.; Khan, Muhammad Saleem. Synthesis, in vitro bio-evaluation, and molecular docking study of thiosemicarbazone-based isatin/bis-Schiffbase hybrid analogues as effective cholinesterase inhibitors.J. Mol. Struct.20231284
     [Google Scholar]
  8. BrierM.R. GordonB. FriedrichsenK. McCarthyJ. SternA. ChristensenJ. OwenC. AldeaP. SuY. HassenstabJ. CairnsN.J. HoltzmanD.M. FaganA.M. MorrisJ.C. BenzingerT.L.S. AncesB.M. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s disease.Sci. Transl. Med.20168338338ra6610.1126/scitranslmed.aaf2362 27169802
     [Google Scholar]
  9. AbbottA. Neuroscience: The plaque plan.Nature2008456721916116410.1038/456161a 19005527
     [Google Scholar]
  10. HardyJ. SelkoeD.J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics.Science2002297558035335610.1126/science.1072994 12130773
     [Google Scholar]
  11. SelkoeD.J. Resolving controversies on the path to Alzheimer’s therapeutics.Nat. Med.20111791060106510.1038/nm.2460 21900936
     [Google Scholar]
  12. LesnéS. KohM.T. KotilinekL. KayedR. GlabeC.G. YangA. GallagherM. AsheK.H. RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory.Nature2006440708235235710.1038/nature04533 16541076
     [Google Scholar]
  13. ZhuY. PengL. HuJ. ChenY. ChenF. Current anti-Alzheimer’s disease effect of natural products and their principal targets.J. Integr. Neurosci.201918332733910.31083/j.jin.2019.03.1105 31601083
     [Google Scholar]
  14. BortolamiM. PandolfiF. De VitaD. CarafaC. MessoreA. Di SantoR. FerociM. CostiR. ChiarottoI. BagettaD. AlcaroS. ColoneM. StringaroA. ScipioneL. New deferiprone derivatives as multi-functional cholinesterase inhibitors: Design, synthesis and in vitro evaluation.Eur. J. Med. Chem.202019811235010.1016/j.ejmech.2020.112350 32380385
     [Google Scholar]
  15. RogawskiM.A. WenkG.L. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease.CNS Drug Rev.20039327530810.1111/j.1527‑3458.2003.tb00254.x 14530799
     [Google Scholar]
  16. Araujo de Oliveira, Ana P.; Romero Colmenares, Victoria C.; Diniz, Renata; Freitas, Jennifer T.J.; da Cruz, Clara M.; Lages, Eduardo B.; Ferreira, Lucas A.M.; Vieira, Rafael P.; Beraldo, Heloisa Memantine-derived schiff bases as transdermal prodrug candidates.ACS Omega202271167811687
     [Google Scholar]
  17. CacabelosR. TakedaM. WinbladB. The glutamatergic system and neurodegeneration in dementia: Preventive strategies in Alzheimer’s disease.Int. J. Geriatr. Psychiatry199914134710.1002/(SICI)1099‑1166(199901)14:1<3:AID‑GPS897>3.0.CO;2‑7 10029935
     [Google Scholar]
  18. WongK.H. RiazM.K. XieY. ZhangX. LiuQ. ChenH. BianZ. ChenX. LuA. YangZ. Review of current strategies for delivering alzheimer’s disease drugs across the blood-brain barrier.Int. J. Mol. Sci.201920238110.3390/ijms20020381 30658419
     [Google Scholar]
  19. DowlingA DwyerJO AdleyCC Antibiotics: Mode of action and mechanism of resistance2017536545
     [Google Scholar]
  20. XuY. ShiY. LeiF. DaiL. A novel and green cellulose-based Schiff base-Cu (II) complex and its excellent antibacterial activity.Carbohydr. Polym.202023011567110.1016/j.carbpol.2019.115671 31887926
     [Google Scholar]
  21. ChakrabortiA.K. BhagatS. RudrawarS. Magnesium perchlorate as an efficient catalyst for the synthesis of imines and phenylhydrazones.Tetrahedron Lett.200445417641764410.1016/j.tetlet.2004.08.097
     [Google Scholar]
  22. SondhiS.M. SinghN. KumarA. LozachO. MeijerL. Synthesis, anti-inflammatory, analgesic and kinase (CDK-1, CDK-5 and GSK-3) inhibition activity evaluation of benzimidazole/benzoxazole derivatives and some Schiff’s bases.Bioorg. Med. Chem.200614113758376510.1016/j.bmc.2006.01.054 16480879
     [Google Scholar]
  23. RawatA. Vijaya Bhaskar ReddyA. Recent advances on anticancer activity of coumarin derivatives.Eur. J. Med. Chem. Rep.2022510003810.1016/j.ejmcr.2022.100038
     [Google Scholar]
  24. LiuJ. BuW. PanL. ShiJ. NIR-triggered anticancer drug delivery by upconverting nanoparticles with integrated azobenzene-modified mesoporous silica.Angew. Chem. Int. Ed.201352164375437910.1002/anie.201300183 23495013
     [Google Scholar]
  25. HaraldG. DietzF.R. Biocatalytic synthesis of natural and non‐natural α‐amino acids.Wiley Encyclopedia of Chemical Biology200810.1002/9780470048672.wecb365
     [Google Scholar]
  26. AnsariK.I. GrantJ.D. KasiriS. WoldemariamG. ShresthaB. MandalS.S. Manganese(III)-salens induce tumor selective apoptosis in human cells.J. Inorg. Biochem.2009103581882610.1016/j.jinorgbio.2009.02.004 19297027
     [Google Scholar]
  27. HaraldG. DietzF.R. Biocatalytic Synthesis of Natural and Non‐Natural α‐Amino Acids.Wiley Encyclopedia of Chemical Biology200810.1002/9780470048672.wecb365
     [Google Scholar]
  28. CordesE.H. JencksW.P. The mechanism of hydrolysis of schiff bases derived from aliphatic amines.J. Am. Chem. Soc.196385182843284810.1021/ja00901a037
     [Google Scholar]
  29. DonosoJ. MuñozF. García Del VadoA. EchevarríaG. García BlancoF. Study of the hydrolysis and ionization constants of Schiff base from pyridoxal 5′-phosphate and n-hexylamine in partially aqueous solvents. An application to phosphorylase b.Biochem. J.1986238113714410.1042/bj2380137 3099764
     [Google Scholar]
  30. FahelJ.S. VieiraR.P. MarinhoF.V. SantosV.C. de AssisJ.V. CorsettiP.P. FerreiraR.S. de AlmeidaM.V. OliveiraS.C. JVA, an isoniazid analogue, is a bioactive compound against a clinical isolate of the mycobacterium avium complex.Tuberculosis2019115108112
     [Google Scholar]
  31. AttiqueS.A. HassanM. UsmanM. AtifR.M. MahboobS. Al-GhanimK.A. BilalM. NawazM.Z. A molecular docking approach to evaluate the pharmacological properties of natural and synthetic treatment candidates for Use against hypertension.Int. J. Environ. Res. Public Health201916692310.3390/ijerph16060923 30875817
     [Google Scholar]
  32. ManjuP.T. Anton SmithA. PadmajaV. In-silico design, synthesis and in-vitro anti-tubercular and anti-microbial screening of novel benzimidazole derivatives.IJPSR20189937053711
     [Google Scholar]
  33. LaskowskiR.A. JabłońskaJ. PravdaL. VařekováR.S. ThorntonJ.M. PDBsum: Structural summaries of PDB entries.Protein Sci.201827112913410.1002/pro.3289 28875543
     [Google Scholar]
  34. HemalathaK. SujathaK. PanneerselvamP. GirijaK. In Silico studies of 4-Anilino quinazoline derivatives as anti-tubercular agents.Int. J. Res. Pharm. Sci.20201147468747510.26452/ijrps.v11i4.3948
     [Google Scholar]
  35. HemalathaK. KamaliR. MalarvizhiM. PragathiS. TamizhmathyM. GirijaK. In silico studies of imidazole derivatives as glucosamine-6-phosphate synthase inhibitors EIPUR202077528539
     [Google Scholar]
  36. BlakeJ.F. LairdE.R. Chppter 30. Recent advances in virtual ligand screening.Annu. Rep. Med. Chem.20033830531410.1016/S0065‑7743(03)38031‑5
     [Google Scholar]
  37. RevathiG. GirijaK. In Silico Design and Solvent Free Synthesis of Some Novel Dihydropyrimidinthione Derivatives and Study of its Antimicrobial Activity.Curr. Trends Biotechnol. Pharm.162111130
     [Google Scholar]
  38. BanerjeePriyanka EckertAndreas O. SchreyAnna K. Preissner, Robert ProTox-II: A webserver for the prediction of toxicity of chemical.Nucleic Acids Res.201846
     [Google Scholar]
  39. EllmanG.L. CourtneyK.D. AndresV.Jr FeatherstoneR.M. A new and rapid colorimetric determination of acetylcholinesterase activity.Biochem. Pharmacol.196172889510.1016/0006‑2952(61)90145‑9 13726518
     [Google Scholar]
  40. ShidoreM. MachhiJ. ShingalaK. MurumkarP. SharmaM.K. AgrawalN. TripathiA. ParikhZ. PillaiP. YadavM.R. Benzylpiperidine-linked diarylthiazoles as potential anti-Alzheimer’s agents: Synthesis and biological evaluation.J. Med. Chem.201659125823584610.1021/acs.jmedchem.6b00426 27253679
     [Google Scholar]
  41. BajadNilesh Gajanan SinghRavi Bhushan Gajendra, T.A.; Gutti, Gopichand; Kumar, Ashok; Krishnamurthy, Sairam; Singh, Sushil Kumar Development of multi-targetable chalcone derivatives bearing N-aryl piperazine moiety for the treatment of Alzheimer’s disease.Bioorg. Chem.202410.1016/j.bioorg.2023.107082
     [Google Scholar]
/content/journals/cbc/10.2174/0115734072326297240919095545
Loading
Design, Synthesis, and Study of Novel Memantine Schiff Base Derivatives against Targeted Enzymes in Alzheimer’s Disease
Curr. Bioact. Compd. 21, e15734072326297 (2025); https://doi.org/10.2174/0115734072326297240919095545
/content/journals/cbc/10.2174/0115734072326297240919095545
/content/journals/cbc/10.2174/0115734072326297240919095545
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher's website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): acetylcholinesterase; Alzheimer’s disease; butyrylcholinesterase; Memantine; molecular docking; Schiff base

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test