Skip to content
2000
Volume 32, Issue 32
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative brain disorder, primarily affecting the elderly. Its socio-economic impact and mortality rate are alarming, necessitating innovative approaches to drug discovery. Unlike single-target diseases, Alzheimer's multifactorial nature makes single-target approaches less effective. To address this challenge, researchers are turning to drug design strategies targeting multiple disease pathways simultaneously. This approach has led to the promising identification of dual or multiple-target inhibitors, offering new perspectives for improving disease management. Computer-Aided Drug Design (CADD) such as virtual screening, docking, QSAR, molecular dynamics, ADMET prediction, ., are valuable tools for designing and identifying new multi target directed ligands (MTDLs). These methods enable efficient screening of extensive compound libraries and accurate prediction of pharmacokinetic profiles, optimizing development costs and time. Challenges such as model accuracy, simulation complexity, and data integration persist. Addressing these issues requires advances in modeling, high-performance computing, and experimental validation. In this regard, this review highlights recent advances using various computational methods to screen and identify new candidate compounds containing different heterocyclic motifs that could serve as potential bases for designing ligands targeting multiple targets for Alzheimer's disease.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673320300240930064551
2025-01-20
2025-10-25

  • From This Site

    /content/journals/cmc/10.2174/0109298673320300240930064551
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. SrivastavaS. AhmadR. KhareS.K. Alzheimer’s disease and its treatment by different approaches: A review.Eur. J. Med. Chem.202121611332010.1016/j.ejmech.2021.11332033652356
     [Google Scholar]
  2. Alzheimer’s Disease International (ADI) World Alzheimer Report 2023: Reducing Dementia Risk: Never too early, never too late.2023Available from: https://www.alzint.org/resource/world-alzheimer-report-2023/
  3. MurmuA. MatoreB.M. KumarN. PandeyN.K. ChhabraN. BanjareL. BasakS. SinghJ. RoyP.P. Role of target fishing in discovery of novel anti-Alzheimer’s agents: In silico applications. In: Deciphering Drug Targets for Alzheimer’s Disease. KumarD. PatilV.M. WuD. ThoratN. SingaporeSpringer Nature202324528410.1007/978‑981‑99‑2657‑2_12
     [Google Scholar]
  4. Andrade-GuerreroJ. Santiago-BalmasedaA. Jeronimo-AguilarP. Vargas-RodríguezI. Cadena-SuárezA.R. Sánchez-GaribayC. Pozo-MolinaG. Méndez-CataláC.F. Cardenas-AguayoM.C. Diaz-CintraS. Pacheco-HerreroM. Luna-MuñozJ. Soto-RojasL.O. Alzheimer’s disease: An updated overview of its genetics.Int. J. Mol. Sci.2023244375410.3390/ijms2404375436835161
     [Google Scholar]
  5. BufillE. BartésA. MoralA. CasadevallT. CodinachsM. ZapaterE. Carles RoviraJ. RouraP. OlivaR. BlesaR. Genetic and environmental factors that may influence in the senile form of Alzheimer’s disease: nested case control studies.Neurologia200924210811219322689
     [Google Scholar]
  6. AyeniE.A. AldossaryA.M. AyejotoD.A. GbadegesinL.A. AlshehriA.A. AlfassamH.A. AfewerkyH.K. AlmughemF.A. BelloS.M. TawfikE.A. Neurodegenerative diseases: Implications of environmental and climatic influences on neurotransmitters and neuronal hormones activities.Int. J. Environ. Res. Public Health202219191249510.3390/ijerph19191249536231792
     [Google Scholar]
  7. BreijyehZ. KaramanR. Comprehensive review on Alzheimer’s disease: Causes and treatment.Molecules20202524578910.3390/molecules2524578933302541
     [Google Scholar]
  8. YadavM.R. MurumkarP.R. BarotR. YadavR. JoshiK. ChauhanM. Role of computational modeling in drug discovery for Alzheimer’s disease. In: Current Trends in Computational Modeling for Drug Discovery20235710710.1007/978‑3‑031‑33871‑7_3
     [Google Scholar]
  9. BriggsR. Dr. S. Kennelly, and D. O’Neill, ‘Drug treatments in Alzheimers disease’.Clin. Med. (Lond.)20161624725310.7861/clinmedicine.16‑3‑24727251914
     [Google Scholar]
  10. YakupovaE.I. BobylevaL.G. ShumeykoS.A. VikhlyantsevI.M. BobylevA.G. Amyloids: The history of toxicity and functionality.Biology (Basel)202110539410.3390/biology1005039434062910
     [Google Scholar]
  11. ForloniG. BalducciC. Alzheimer’s disease, oligomers, and inflammation.J. Alzheimers Dis.20186231261127610.3233/JAD‑17081929562537
     [Google Scholar]
  12. NaseriN.N. WangH. GuoJ. SharmaM. LuoW. The complexity of tau in Alzheimer’s disease.Neurosci. Lett.201970518319410.1016/j.neulet.2019.04.02231028844
     [Google Scholar]
  13. KumarN. KumarV. AnandP. KumarV. Ranjan DwivediA. KumarV. Advancements in the development of multi-target directed ligands for the treatment of Alzheimer’s disease.Bioorg. Med. Chem.20226111674210.1016/j.bmc.2022.11674235398739
     [Google Scholar]
  14. GabrM.T. IbrahimM.M. Multitarget therapeutic strategies for Alzheimer’s disease.Neural Regen. Res.201914343744010.4103/1673‑5374.24546330539809
     [Google Scholar]
  15. SangZ. WangK. DongJ. TangL. Alzheimer’s disease: Updated multi-targets therapeutics are in clinical and in progress.Eur. J. Med. Chem.202223811446410.1016/j.ejmech.2022.11446435635955
     [Google Scholar]
  16. GongC.X. DaiC.L. LiuF. IqbalK. Multi-targets: An unconventional drug development strategy for Alzheimer’s disease.Front. Aging Neurosci.20221483764910.3389/fnagi.2022.83764935222001
     [Google Scholar]
  17. GratuzeM. LeynsC.E.G. HoltzmanD.M. New insights into the role of TREM2 in Alzheimer’s disease.Mol. Neurodegener.20181316610.1186/s13024‑018‑0298‑930572908
     [Google Scholar]
  18. GunesS. AizawaY. SugashiT. SugimotoM. RodriguesP.P. Biomarkers for Alzheimer’s disease in the current state: A narrative review.Int. J. Mol. Sci.2022239496210.3390/ijms2309496235563350
     [Google Scholar]
  19. CummingsJ. ZhouY. LeeG. ZhongK. FonsecaJ. ChengF. Alzheimer’s disease drug development pipeline: 2024.Alzheimers Dement. (N. Y.)2024102e1246510.1002/trc2.1246538659717
     [Google Scholar]
  20. FangJ. LiY. LiuR. PangX. LiC. YangR. HeY. LianW. LiuA.L. DuG.H. Discovery of multitarget-directed ligands against Alzheimer’s disease through systematic prediction of chemical-protein interactions.J. Chem. Inf. Model.201555114916410.1021/ci500574n25531792
     [Google Scholar]
  21. CheongS.L. TiewJ.K. FongY.H. LeongH.W. ChanY.M. ChanZ.L. KongE.W.J. Current pharmacotherapy and multi-target approaches for Alzheimer’s disease.Pharmaceuticals (Basel)20221512156010.3390/ph1512156036559010
     [Google Scholar]
  22. MouchlisV.D. MelagrakiG. ZachariaL.C. AfantitisA. Computer-aided drug design of β-secretase, γ-secretase and anti-tau inhibitors for the discovery of novel Alzheimer’s therapeutics.Int. J. Mol. Sci.202021370310.3390/ijms2103070331973122
     [Google Scholar]
  23. NiuY. LinP. Advances of computer-aided drug design (CADD) in the development of anti-Azheimer’s-disease drugs.Drug Discov. Today202328810366510.1016/j.drudis.2023.10366537302540
     [Google Scholar]
  24. BhattacharyaK. DevanathB. DasD. ChanuN.R. BhattacharjeeA. Recent developments in the application of computer-aided drug design in neurodegenerative disorders. In: Computational Methods in Psychiatry. BattineniG. MittalM. ChintalapudiN. SingaporeSpringer Nature202322725810.1007/978‑981‑99‑6637‑0_12
     [Google Scholar]
  25. BaigM.H. AhmadK. RabbaniG. DanishuddinM. ChoiI. Computer aided drug design and its application to the development of potential drugs for neurodegenerative disorders.Curr. Neuropharmacol.201816674074810.2174/1570159X1566617101616351029046156
     [Google Scholar]
  26. AbchirO. DaouiO. NourH. YamariI. ElkhattabiS. ErrouguiA. ChtitaS. Exploration of Cannabis constituents as potential candidates against diabetes mellitus disease using molecular docking, dynamics simulations and ADMET investigations.Sci. Am.202321e0174510.1016/j.sciaf.2023.e01745
     [Google Scholar]
  27. AbchirO. NourH. DaouiO. YamariI. ElKhattabiS. El KoualiM. TalbiM. ErrouguiA. ChtitaS. Structure-based virtual screening, ADMET analysis, and molecular dynamics simulation of Moroccan natural compounds as candidates for the SARS-CoV-2 inhibitors.Nat. Prod. Res.2023001810.1080/14786419.2023.228100237966948
     [Google Scholar]
  28. AbchirO. YamariI. ShtaiwiA.M. NourH. KoualiM.E. TalbiM. ErrouguiA. ChtitaS. Insights into the inhibitory potential of novel hydrazinyl thiazole-linked indenoquinoxaline against alpha-amylase: a comprehensive QSAR, pharmacokinetic, and molecular modeling study.J. Biomol. Struct. Dyn.20240011810.1080/07391102.2024.231077838305802
     [Google Scholar]
  29. AbchirO. KhedraouiM. NourH. YamariI. ErrouguiA. SamadiA. ChtitaS. Integrative approach for designing novel triazole derivatives as α-glucosidase inhibitors: QSAR, molecular docking, ADMET, and molecular dynamics investigations.Pharmaceuticals (Basel)202417226110.3390/ph1702026138399476
     [Google Scholar]
  30. YamariI. AbchirO. NourH. El KoualiM. ChtitaS. Identification of new dihydrophenanthrene derivatives as promising anti-SARS-CoV-2 drugs through in silico investigations.Main Group Chem.202322346948410.3233/MGC‑220127
     [Google Scholar]
  31. YamariI. AbchirO. MaliS.N. ErrouguiA. TalbiM. KoualiM.E. ChtitaS. The anti-SARS-CoV-2 activity of novel 9, 10-dihydrophenanthrene derivatives: an insight into molecular docking, ADMET analysis, and molecular dynamics simulation.Sci. Am.202321e0175410.1016/j.sciaf.2023.e0175437332393
     [Google Scholar]
  32. YamariI. MouhibA. Es-SounniB. NejjariR. MazoirN. BakhouchM. MouzdahirA. BenharrefA. El KoualiM. ChtitaS. Oxidative functionalization of triterpenes isolated from Euphorbia resinifera latex: Semisynthesis, ADME-Tox, molecular docking, and molecular dynamics simulations.Chemical Physics Impact2023710037210.1016/j.chphi.2023.100372
     [Google Scholar]
  33. YamariI. SurajN.M. AbchirO. NourH. GmouhS. El KoualiM.H. ChtitaS. In silico investigations of dihydrophenanthrene derivatives as potential inhibitors of SARS-CoV-2 Med.Sci. Forum202214112110.3390/ECMC2022‑13293
     [Google Scholar]
  34. NourH. AbchirO. BelaidiS. QaisF.A. ChtitaS. BelaaouadS. 2D‐QSAR and molecular docking studies of carbamate derivatives to discover novel potent anti‐butyrylcholinesterase agents for Alzheimer’s disease treatment.Bull. Korean Chem. Soc.202243227729210.1002/bkcs.12449
     [Google Scholar]
  35. NourH. HashmiM.A. BelaidiS. ErrouguiA. El KoualiM. TalbiM. ChtitaS. Design of acetylcholinesterase inhibitors as promising anti‐Alzheimer’s agents based on QSAR, molecular docking, and molecular dynamics studies of liquiritigenin derivatives.ChemistrySelect2023832e20230146610.1002/slct.202301466
     [Google Scholar]
  36. NourH. AbdouA. BelaidiS. JamalJ.E. ElmakssoudiA. DakirM. ChtitaS. Discovery of promising cholinesterase inhibitors for Alzheimer’s disease treatment through DFT, docking, and molecular dynamics studies of eugenol derivatives.J. Chin. Chem. Soc. (Taipei)20226991534155110.1002/jccs.202200195
     [Google Scholar]
  37. KhedraouiM. NourH. YamariI. AbchirO. ErrouguiA. ChtitaS. Design of a new potent Alzheimer’s disease inhibitor based on QSAR, molecular docking and molecular dynamics investigations.Chemical Physics Impact2023710036110.1016/j.chphi.2023.100361
     [Google Scholar]
  38. SamadiA. EstradaM. PérezC. Rodríguez-FrancoM.I. IriepaI. MoraledaI. ChiouaM. Marco-ContellesJ. Pyridonepezils, new dual AChE inhibitors as potential drugs for the treatment of Alzheimer’s disease: Synthesis, biological assessment, and molecular modeling.Eur. J. Med. Chem.20125729630110.1016/j.ejmech.2012.09.03023078965
     [Google Scholar]
  39. SamadiA. Marco-ContellesJ. SorianoE. Álvarez-PérezM. ChiouaM. RomeroA. González-LafuenteL. GandíaL. RodaJ.M. LópezM.G. VillarroyaM. GarcíaA.G. RíosC. Multipotent drugs with cholinergic and neuroprotective properties for the treatment of Alzheimer and neuronal vascular diseases. I. Synthesis, biological assessment, and molecular modeling of simple and readily available 2-aminopyridine-, and 2-chloropyridine-3,5-dicarbonitriles.Bioorg. Med. Chem.201018165861587210.1016/j.bmc.2010.06.09520656495
     [Google Scholar]
  40. NourH. YamariI. AbchirO. MounadiN. SamadiA. BelaidiS. ChtitaS. Exploring Cannabis sativa L for Anti-Alzheimer Potential: An extensive computational study including molecular docking, molecular dynamics, and ADMET assessments.202410.21203/rs.3.rs‑3986384/v1
     [Google Scholar]
  41. GoyalD. KaurA. GoyalB. Benzofuran and indole: Promising scaffolds for drug development in Alzheimer’s disease.ChemMedChem201813131275129910.1002/cmdc.20180015629742314
     [Google Scholar]
  42. GeorgeN. Jawaid AkhtarM. Al BalushiK.A. Alam KhanS. Rational drug design strategies for the development of promising multi-target directed indole hybrids as Anti-Alzheimer agents.Bioorg. Chem.202212710594110.1016/j.bioorg.2022.10594135714473
     [Google Scholar]
  43. GuptaS.M. BeheraA. JainN.K. TripathiA. RishipathakD. SinghS. AhemadN. ErolM. KumarD. Development of substituted benzylidene derivatives as novel dual cholinesterase inhibitors for Alzheimer’s treatment.RSC Advances20231338263442635610.1039/D3RA03224H37671344
     [Google Scholar]
  44. ShaikhS. PavaleG. DhavanP. SinghP. UparkarJ. VaidyaS.P. JadhavB.L. RamanaM.M.V. Design, synthesis and evaluation of dihydropyranoindole derivatives as potential cholinesterase inhibitors against Alzheimer’s disease.Bioorg. Chem.202111010477010.1016/j.bioorg.2021.10477033667902
     [Google Scholar]
  45. YıldızM. BingulM. ZorluY. SaglamM.F. BogaM. TemelM. KocaM.S. KandemirH. SengulI.F. Dimethoxyindoles based thiosemicarbazones as multi-target agents; synthesis, crystal interactions, biological activity and molecular modeling.Bioorg. Chem.202212010564710.1016/j.bioorg.2022.10564735121556
     [Google Scholar]
  46. NerellaA. JeripothulaM. Design, synthesis and biological evaluation of novel deoxyvasicinone-indole as multi-target agents for Alzheimer’s disease.Bioorg. Med. Chem. Lett.20214912821210.1016/j.bmcl.2021.12821234153471
     [Google Scholar]
  47. PourtaherH. HasaninejadA. ZareS. TanidehN. IrajiA. The anti-Alzheimer potential of novel spiroindolin-1,2-diazepine derivatives as targeted cholinesterase inhibitors with modified substituents.Sci. Rep.20231311195210.1038/s41598‑023‑38236‑037488177
     [Google Scholar]
  48. MishraC.B. GusainS. ShaliniS. KumariS. PrakashA. KumariN. YadavA.K. KumariJ. KumarK. TiwariM. Development of novel carbazole derivatives with effective multifunctional action against Alzheimer’s diseases: Design, synthesis, in silico, in vitro and in vivo investigation.Bioorg. Chem.20209510352410.1016/j.bioorg.2019.10352431918396
     [Google Scholar]
  49. LamieP.F. Abdel-FattahM.M. PhiloppesJ.N. Design and synthesis of new indole drug candidates to treat Alzheimer’s disease and targeting neuro-inflammation using a multi-target-directed ligand (MTDL) strategy.J. Enzyme Inhib. Med. Chem.20223712660267810.1080/14756366.2022.212646436146947
     [Google Scholar]
  50. ZhouL.C. LiangY.F. HuangY. YangG.X. ZhengL.L. SunJ.M. LiY. ZhuF.L. QianH.W. WangR. MaL. Design, synthesis, and biological evaluation of diosgenin-indole derivatives as dual-functional agents for the treatment of Alzheimer’s disease.Eur. J. Med. Chem.202121911342610.1016/j.ejmech.2021.11342633848787
     [Google Scholar]
  51. PatelD.V. PatelN.R. KanhedA.M. PatelS.P. SinhaA. KansaraD.D. MecwanA.R. PatelS.B. UpadhyayP.N. PatelK.B. ShahD.B. PrajapatiN.K. MurumkarP.R. PatelK.V. YadavM.R. Novel multitarget directed triazinoindole derivatives as anti-Alzheimer agents.ACS Chem. Neurosci.20191083635366110.1021/acschemneuro.9b0022631310717
     [Google Scholar]
  52. PatelD.V. PatelN.R. KanhedA.M. TeliD.M. PatelK.B. GandhiP.M. PatelS.P. ChaudharyB.N. ShahD.B. PrajapatiN.K. PatelK.V. YadavM.R. Further studies on triazinoindoles as potential novel multitarget-directed anti-Alzheimer’s agents.ACS Chem. Neurosci.202011213557357410.1021/acschemneuro.0c0044833073564
     [Google Scholar]
  53. LanthierC. PayanH. LiparuloI. HatatB. LecouteyC. SinceM. DavisA. BergaminiC. ClaeysenS. DallemagneP. BolognesiM.L. RochaisC. Novel multi target-directed ligands targeting 5-HT4 receptors with in cellulo antioxidant properties as promising leads in Alzheimer’s disease.Eur. J. Med. Chem.201918211159610.1016/j.ejmech.2019.11159631419776
     [Google Scholar]
  54. LalutJ. PayanH. DavisA. LecouteyC. LegayR. Sopkova-de Oliveira SantosJ. ClaeysenS. DallemagneP. RochaisC. Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT4 receptors activities for the treatment of Alzheimer’s disease.Sci. Rep.2020101301410.1038/s41598‑020‑59805‑731913322
     [Google Scholar]
  55. WichurT. PasiekaA. GodyńJ. PanekD. GóralI. LataczG. Honkisz-OrzechowskaE. BuckiA. SiwekA. Głuch-LutwinM. KnezD. BrazzolottoX. GobecS. KołaczkowskiM. SabateR. MalawskaB. WięckowskaA. Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT6 receptor with anti-aggregation properties against amyloid-beta and tau.Eur. J. Med. Chem.202122511378310.1016/j.ejmech.2021.11378334461507
     [Google Scholar]
  56. PurgatorioR. GambacortaN. CattoM. de CandiaM. PisaniL. EspargaróA. SabatéR. CellamareS. NicolottiO. AltomareC. Pharmacophore modeling and 3D-QSAR study of indole and isatin derivatives as antiamyloidogenic agents targeting Alzheimer’s disease.Molecules20202523577310.3390/molecules2523577333297547
     [Google Scholar]
  57. HusainA. BalushiK.A. AkhtarM.J. KhanS.A. Coumarin linked heterocyclic hybrids: A promising approach to develop multi target drugs for Alzheimer’s disease.J. Mol. Struct.2021124113061810.1016/j.molstruc.2021.130618
     [Google Scholar]
  58. VermaV. KumarN. KumarS. Anti-Alzheimer potential of coumarin derivatives: A review.World J. Adv. Res. Rev.202320182583510.30574/wjarr.2023.20.1.2094
     [Google Scholar]
  59. GeorgeN. SabahiB.A. AbuKhaderM. BalushiK.A. AkhtarM.J. KhanS.A. Design, synthesis and in vitro biological activities of coumarin linked 1,3,4-oxadiazole hybrids as potential multi-target directed anti-Alzheimer agents.J. King Saud Univ. Sci.202234410197710.1016/j.jksus.2022.101977
     [Google Scholar]
  60. BehlT. KaurD. SehgalA. SinghS. SharmaN. ZenginG. Andronie-CioaraF.L. TomaM.M. BungauS. BumbuA.G. Role of monoamine oxidase activity in Alzheimer’s disease: An insight into the therapeutic potential of inhibitors.Molecules20212612372410.3390/molecules2612372434207264
     [Google Scholar]
  61. MzezewaS.C. OmoruyiS.I. ZondaghL.S. MalanS.F. EkpoO.E. JoubertJ. Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents.J. Enzyme Inhib. Med. Chem.20213611606162010.1080/14756366.2021.191313734281458
     [Google Scholar]
  62. BabaeiE. KüçükkılınçT.T. Jalili-BalehL. NadriH. ÖzE. ForootanfarH. HosseinzadehE. AkbariT. ArdestaniM.S. FiroozpourL. Novel coumarin-pyridine hybrids as potent multi-target directed ligands aiming at symptoms of Alzheimer’s disease.Front Chem.20221089548310.3389/fchem.2022.895483
     [Google Scholar]
  63. GuoJ. MiZ. JiangX. ZhangC. GuoZ. LiL. GuJ. ZhouT. BaiR. XieY. Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects.Bioorg. Chem.202110810456410.1016/j.bioorg.2020.10456433353806
     [Google Scholar]
  64. YangA. ZhangH. HuC. WangX. ShenR. KouX. WangH. Novel coumarin derivatives as multifunctional anti-AD agents: Design, synthesis, X-ray crystal structure and biological evaluation.J. Mol. Struct.2022126813374710.1016/j.molstruc.2022.133747
     [Google Scholar]
  65. AgboE.N. GildenhuysS. ChoongY.S. MphahleleM.J. MoreG.K. Synthesis of furocoumarin–stilbene hybrids as potential multifunctional drugs against multiple biochemical targets associated with Alzheimer’s disease.Bioorg. Chem.202010110399710.1016/j.bioorg.2020.10399732554280
     [Google Scholar]
  66. PourabdiL. KüçükkılınçT.T. KhoshtaleF. AyazgökB. NadriH. Farokhi AlashtiF. ForootanfarH. AkbariT. ShafieiM. ForoumadiA. SharifzadehM. Shafiee ArdestaniM. AbaeeM.S. FiroozpourL. KhoobiM. MojtahediM.M. Synthesis of new 3-arylcoumarins bearing N-benzyl triazole moiety: Dual lipoxygenase and butyrylcholinesterase inhibitors with anti-amyloid aggregation and neuroprotective properties against Alzheimer’s disease.Front Chem.2022981023310.3389/fchem.2021.81023335127652
     [Google Scholar]
  67. Karimi AskaraniH. IrajiA. RastegariA. Abbas BukhariS.N. FiruziO. AkbarzadehT. SaeediM. Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer’s disease.BMC Chem.20201416410.1186/s13065‑020‑00715‑033134975
     [Google Scholar]
  68. BoulaamaneY. KandpalP. ChandraA. BritelM.R. MauradyA. Chemical library design, QSAR modeling and molecular dynamics simulations of naturally occurring coumarins as dual inhibitors of MAO-B and AChE.J. Biomol. Struct. Dyn.202342411810.1080/07391102.2023.220965037199265
     [Google Scholar]
  69. EckroatT.J. ManrossD.L. CowanS.C. Merged tacrine-based, multitarget-directed acetylcholinesterase inhibitors 2015–present: Synthesis and biological activity.Int. J. Mol. Sci.20202117596510.3390/ijms2117596532825138
     [Google Scholar]
  70. ZhangP. WangZ. MouC. ZouJ. XieY. LiuZ. Benjamin NamanC. MaoY. WeiJ. HuangX. DongJ. YangM. WangN. JinH. LiuF. LinD. LiuH. ZhouF. HeS. ZhangB. CuiW. Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer’s disease.Bioorg. Chem.202111610538710.1016/j.bioorg.2021.10538734628225
     [Google Scholar]
  71. FaresS. El HusseinyW.M. SelimK.B. MassoudM.A.M. Modified tacrine derivatives as multitarget-directed ligands for the treatment of Alzheimer’s disease: Synthesis, biological evaluation, and molecular modeling study.ACS Omega2023829260122603410.1021/acsomega.3c0205137521639
     [Google Scholar]
  72. FancelluG. ChandK. TomásD. OrlandiniE. PiemonteseL. SilvaD.F. CardosoS.M. ChavesS. SantosM.A. Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s disease.J. Enzyme Inhib. Med. Chem.202035121122610.1080/14756366.2019.168923731760822
     [Google Scholar]
  73. UliassiE. BergaminiC. RizzardiN. NaldiM. CoresÁ. BartoliniM. Carlos MenéndezJ. BolognesiM.L. Quinolinetrione-tacrine hybrids as multi-target-directed ligands against Alzheimer’s disease.Bioorg. Med. Chem.20239111741910.1016/j.bmc.2023.11741937487339
     [Google Scholar]
  74. LongJ. QinF. LuoJ. ZhongG. HuangS. JingL. YiT. LiuJ. JiangN. Design, synthesis, and biological evaluation of novel capsaicin-tacrine hybrids as multi-target agents for the treatment of Alzheimer’s disease.Bioorg. Chem.202414310702610.1016/j.bioorg.2023.10702638103330
     [Google Scholar]
  75. NepovimovaE. SvobodovaL. DolezalR. HepnarovaV. JunovaL. JunD. KorabecnyJ. KuceraT. GazovaZ. MotykovaK. KubackovaJ. BednarikovaZ. JanockovaJ. JesusC. CortesL. PinaJ. RostoharD. SerpaC. SoukupO. AitkenL. HughesR.E. MusilekK. MuckovaL. JostP. ChvojkovaM. ValesK. ValisM. ChrienovaZ. ChalupovaK. KucaK. Tacrine – Benzothiazoles: Novel class of potential multitarget anti-Alzheimeŕs drugs dealing with cholinergic, amyloid and mitochondrial systems.Bioorg. Chem.202110710459610.1016/j.bioorg.2020.10459633421953
     [Google Scholar]
  76. LiuZ. ZhangB. XiaS. FangL. GouS. ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.Eur. J. Med. Chem.202121211299710.1016/j.ejmech.2020.11299733189440
     [Google Scholar]
  77. SharmaS. ChauhanN. PaliwalS. JainS. VermaK. PaliwalS. GSK-3β and its inhibitors in Alzheimer’s disease: A recent update.Mini Rev. Med. Chem.202222222881289510.2174/138955752266622042009431735450523
     [Google Scholar]
  78. YaoH. UrasG. ZhangP. XuS. YinY. LiuJ. QinS. LiX. AllenS. BaiR. GongQ. ZhangH. ZhuZ. XuJ. Discovery of novel tacrine–pyrimidone hybrids as potent dual AChE/GSK-3 inhibitors for the treatment of Alzheimer’s disease.J. Med. Chem.202164117483750610.1021/acs.jmedchem.1c0016034024109
     [Google Scholar]
  79. El fadili, M.; Er-rajy, M.; Abdalla, M.; Abuelizz, H.A.; Zarougui, S.; Alkhulaifi, F.M.; Alahmady, N.F.; Shami, A.; Elhallaoui, M. In-silico investigations of novel tacrine derivatives potency against Alzheimer’s disease.Sci. Afr.202423e0204810.1016/j.sciaf.2023.e02048
     [Google Scholar]
  80. LiQ. HeS. ChenY. FengF. QuW. SunH. Donepezil-based multi-functional cholinesterase inhibitors for treatment of Alzheimer’s disease.Eur. J. Med. Chem.201815846347710.1016/j.ejmech.2018.09.03130243151
     [Google Scholar]
  81. QuedaF. CalòS. GwizdalaK. MagalhãesJ.D. CardosoS.M. ChavesS. PiemonteseL. SantosM.A. Novel donepezil–arylsulfonamide hybrids as multitarget-directed ligands for potential treatment of Alzheimer’s disease.Molecules2021266165810.3390/molecules2606165833809771
     [Google Scholar]
  82. DuH. LiuX. XieJ. MaF. Novel deoxyvasicinone–donepezil hybrids as potential multitarget drug candidates for Alzheimer’s disease.ACS Chem. Neurosci.20191052397240710.1021/acschemneuro.8b0069930720268
     [Google Scholar]
  83. WanD. WangF.Q. XieJ. ChenL. ZhouX.L. Design, synthesis, and biological activity of donepezil: Aromatic amine hybrids as anti-Alzheimerss drugs.ACS Omega2023824218022181210.1021/acsomega.3c0142737360465
     [Google Scholar]
  84. ZhouY. HeY. TengX. MiJ. YangJ. WeiR. LiuW. MaQ. TanZ. SangZ. Development of novel salicylic acid–donepezil–rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease.J. Enzyme Inhib. Med. Chem.2023381223166110.1080/14756366.2023.223166137414563
     [Google Scholar]
  85. SangZ. BaiP. BanY. WangK. WuA. MiJ. HuJ. XuR. ZhuG. WangJ. ZhangJ. WangC. TanZ. TangL. Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer’s agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies.Bioorg. Chem.202212710600710.1016/j.bioorg.2022.10600735849893
     [Google Scholar]
  86. TurkanF. CetinA. TaslimiP. KaramanM. Gulçinİ. Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors.Bioorg. Chem.20198642042710.1016/j.bioorg.2019.02.01330769267
     [Google Scholar]
  87. KanwalM. SarwarS. NadeemH. ZafarR. RahmanK.M. Synthesis of Pyrazoline derivatives, condensation of β-dicarbonyl compounds with isoniazid (INH), and their biological evaluation as multitarget anti-Alzheimer’ disease agents.Chem. Pap.2024782033204210.1007/s11696‑023‑03224‑1
     [Google Scholar]
  88. GuttiG. KakarlaR. KumarD. BeoharM. GaneshpurkarA. KumarA. KrishnamurthyS. SinghS.K. Discovery of novel series of 2-substituted benzo[d]oxazol-5-amine derivatives as multi-target directed ligands for the treatment of Alzheimer’s disease.Eur. J. Med. Chem.201918211161310.1016/j.ejmech.2019.11161331437780
     [Google Scholar]
  89. GhobadianR. MahdaviM. NadriH. MoradiA. EdrakiN. AkbarzadehT. SharifzadehM. BukhariS.N.A. AminiM. Novel tetrahydrocarbazole benzyl pyridine hybrids as potent and selective butryl cholinesterase inhibitors with neuroprotective and β-secretase inhibition activities.Eur. J. Med. Chem.2018155496010.1016/j.ejmech.2018.05.03129857276
     [Google Scholar]
  90. TokF. SağlıkB.N. ÖzkayY. KaplancıklıZ.A. Koçyiğit-KaymakçıoğluB. Design, synthesis, biological activity evaluation and in silico studies of new nicotinohydrazide derivatives as multi-targeted inhibitors for Alzheimer’s disease.J. Mol. Struct.2022126513344110.1016/j.molstruc.2022.133441
     [Google Scholar]
  91. ZondaghL.S. MalanS.F. JoubertJ. Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents.J. Enzyme Inhib. Med. Chem.20203511596160510.1080/14756366.2020.180167332779503
     [Google Scholar]
  92. UmarT. ShaliniS. RazaM.K. GusainS. KumarJ. SethP. TiwariM. HodaN. A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer’s disease.Eur. J. Med. Chem.201917521910.1016/j.ejmech.2019.04.03831055149
     [Google Scholar]
  93. WalyO.M. El-SayedS.M. GhalyM.A. El-SubbaghH.I. Multi-targeted anti-Alzheimer’s agents: Synthesis, biological evaluation, and molecular modeling study of some pyrazolopyridine hybrids.Eur. J. Med. Chem.202326211588010.1016/j.ejmech.2023.11588037871406
     [Google Scholar]
  94. HaghighijooZ. ZamaniL. MoosaviF. EmamiS. Therapeutic potential of quinazoline derivatives for Alzheimer’s disease: A comprehensive review.Eur. J. Med. Chem.202222711394910.1016/j.ejmech.2021.11394934742016
     [Google Scholar]
  95. MoftahH.K. MousaM.H.A. ElrazazE.Z. KamelA.S. LasheenD.S. GeorgeyH.H. Novel quinazolinone Derivatives: Design, synthesis and in vivo evaluation as potential agents targeting Alzheimer disease.Bioorg. Chem.202414310706510.1016/j.bioorg.2023.10706538150939
     [Google Scholar]
  96. LvL. MaimaitimingM. HuangY. YangJ. ChenS. SunY. ZhangX. LiX. XueC. WangP. WangC.Y. LiuZ. Discovery of quinazolin-4(3H)-one derivatives as novel AChE inhibitors with anti-inflammatory activities.Eur. J. Med. Chem.202325411534610.1016/j.ejmech.2023.11534637043994
     [Google Scholar]
  97. HamulakovaS. JanovecL. SoukupO. JunD. JanockovaJ. HrabinovaM. SepsovaV. KucaK. Tacrine-coumarin and tacrine-7-chloroquinoline hybrids with thiourea linkers: Cholinesterase inhibition properties, kinetic study, molecular docking and permeability assay for blood-brain barrier.Curr. Alzheimer Res.201815121096110510.2174/156720501566618071111075029992880
     [Google Scholar]
  98. MatoševićA. OpsenicaD.M. SpasićM. MarakovićN. ZandonaA. ŽunecS. BartolićM. KovarikZ. BosakA. Evaluation of 4-aminoquinoline derivatives with an n-octylamino spacer as potential multi-targeting ligands for the treatment of Alzheimer’s disease.Chem. Biol. Interact.202338211062010.1016/j.cbi.2023.11062037406982
     [Google Scholar]
  99. KomatovićK. MatoševićA. Terzić-JovanovićN. ŽunecS. ŠeganS. ZlatovićM. MarakovićN. BosakA. OpsenicaD.M. 4-aminoquinoline-based adamantanes as potential anticholinesterase agents in symptomatic treatment of Alzheimer’s disease.Pharmaceutics2022146130510.3390/pharmaceutics1406130535745878
     [Google Scholar]
  100. ChenH. MiJ. LiS. LiuZ. YangJ. ChenR. WangY. BanY. ZhouY. DongW. Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease.J. Enzyme Inhib. Med. Chem.2023381216968210.1080/14756366.2023.2169682
     [Google Scholar]
  101. KappenbergY.G. NogaraP.A. StefanelloF.S. DelgadoC.P. RochaJ.B.T. ZanattaN. MartinsM.A.P. BonacorsoH.G. 1,2,3-Triazolo[4,5-b]aminoquinolines: Design, synthesis, structure, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity, and molecular docking of novel modified tacrines.Bioorg. Chem.202313910670410.1016/j.bioorg.2023.10670437453239
     [Google Scholar]
  102. ObaidR.J. MughalE.U. NaeemN. Al-RooqiM.M. SadiqA. JassasR.S. MoussaZ. AhmedS.A. Pharmacological significance of nitrogen-containing five and six-membered heterocyclic scaffolds as potent cholinesterase inhibitors for drug discovery.Process Biochem.202212025025910.1016/j.procbio.2022.06.009
     [Google Scholar]
  103. SilalaiP. JaipeaS. TocharusJ. AthipornchaiA. SuksamrarnA. SaeengR. New 1,2,3-triazole-genipin analogues and their anti-Alzheimer’s activity.ACS Omega2022728243022431610.1021/acsomega.2c0159335874205
     [Google Scholar]
  104. LiuW. TianL. WuL. ChenH. WangN. LiuX. ZhaoC. WuZ. JiangX. WuQ. XuZ. LiuW. ZhaoQ. Discovery of novel β-carboline-1,2,3-triazole hybrids as AChE/GSK-3β dual inhibitors for Alzheimer’s disease treatment.Bioorg. Chem.202212910616810.1016/j.bioorg.2022.10616836191431
     [Google Scholar]
  105. PalT. BhimaneniS. SharmaA. FloraS.J.S. Design, synthesis, biological evaluation and molecular docking study of novel pyridoxine–triazoles as anti-Alzheimer’s agents.RSC Advances20201044260062602110.1039/D0RA04942E35519785
     [Google Scholar]
  106. WangM. FangL. LiuT. ChenX. ZhengY. ZhangY. ChenS. LiZ. Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer’s disease.Chem. Biol. Interact.202134210948910.1016/j.cbi.2021.10948933905740
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673320300240930064551
Loading
Computational Approaches for Multitarget Drug Design in Alzheimer's Disease: A Comprehensive Review
Curr. Med. Chem. 32, 7017 (2025); https://doi.org/10.2174/0109298673320300240930064551
/content/journals/cmc/10.2174/0109298673320300240930064551
/content/journals/cmc/10.2174/0109298673320300240930064551
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): Alzheimer's disease; CADD; dementia; drug discovery; heterocyclic motifs; MTDLs

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