Multitarget therapeutic approaches for Alzheimer's and Parkinson's diseases: an opportunity or an illusion?

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1. Walker L, McAleese KE, Erskine D, Attems J. Neurodegenerative diseases and ageing. Subcell. Biochem. 91, 75–106 (2019). • Describes the main neuropathological features of the most common age-associated neurodegenerative diseases.
  Medline CASGoogle Scholar
• 2. Rodriguez S, Hug C, Todorov P et al. Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat. Commun. 12, 1033 (2021).
  Medline CASGoogle Scholar
• 3. Mulvihill JEJ, Cunnane EM, Ross AM et al. Drug delivery across the blood–brain barrier: recent advances in the use of nanocarriers. Nanomedicine 15(2), 205–214 (2020). •• Provides comprehensive insight into the most recent advancements in nanocarrier-based drug delivery to the CNS, such as the development of multifunctional nanomedicines and theranostics.
  Medline CASGoogle Scholar
• 4. Chen Y-X, Wei C-X, Lyu Y-Q et al. Biomimetic drug-delivery systems for the management of brain diseases. Biomater. Sci. 8, 1073–1088 (2020).
  Medline CASGoogle Scholar
• 5. Kovacs GG. Molecular pathology of neurodegenerative diseases: principles and practice. J. Clin. Pathol. 72(11), 725–735 (2019).
  Medline CASGoogle Scholar
• 6. Ramsay RR, Popovic-Nikolic MR, Nikolic K et al. A perspective on multi-target drug discovery and design for complex diseases. Clin. Transl. Med. 7(1), 3 (2018). • Focuses on the molecular and computational approaches that underpin drug design by medicinal chemists to promote understanding and collaboration with clinical scientists.
  MedlineGoogle Scholar
• 7. Makhouri FR, Ghasemi JB. In silico studies in drug research against neurodegenerative diseases. Curr. Neuropharmacol. 16(6), 664–725 (2018).
  Medline CASGoogle Scholar
• 8. Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 17(1), 230 (2017). • Identifies and summarizes polypharmacy definitions in existing literature.
  MedlineGoogle Scholar
• 9. Rodríguez-Enríquez F, Viña D, Uriarte E et al. 7-amidocoumarins as multitarget agents against neurodegenerative diseases: substitution pattern modulation. ChemMedChem 16, 179–186 (2021).
  Medline CASGoogle Scholar
• 10. Kabir MT, Uddin MS, Mamun AA et al. Combination drug therapy for the management of Alzheimer's Disease. Int. J. Mol. Sci. 21, 3272 (2020).
  CASGoogle Scholar
• 11. Melchiorre C, Andrisano V, Bolognesi ML et al. Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease. J. Med. Chem. 41, 4186–4189 (1998).
  Medline CASGoogle Scholar
• 12. Savelieff MG, Nam G, Kang J et al. Development of multifunctional molecules as potential therapeutic candidates for Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in the last decade. Chem. Rev. 119, 1221–1322 (2019). •• Focuses on the development of multifunctional compounds capable of simultaneously interacting with several pathological components as a solution to the complex pathologies of neurodegenerative diseases.
  Medline CASGoogle Scholar
• 13. Armstrong MJ, Okun MS. Diagnosis and treatment of Parkinson disease: a review. JAMA 323(6), 548–560 (2020). • Reviews the diagnosis and treatment of Parkinson disease.
  MedlineGoogle Scholar
• 14. Tambasco N, Romoli M, Calabresi P. Levodopa in Parkinson's disease: current status and future developments. Curr. Neuropharmacol. 16(8), 1239–1252 (2018).
  Medline CASGoogle Scholar
• 15. Alonso Cánovas A, Luquin Piudo R, García Ruiz-Espiga P et al. Dopaminergic agonists in Parkinson's disease. Neurologia 29(4), 230–241 (2014).
  MedlineGoogle Scholar
• 16. Weinreb O, Amit T, Riederer P et al. Neuroprotective profile of the multitarget drug rasagiline in Parkinson's disease. Int. Rev. Neurobiol. 100, 127–149 (2011).
  Medline CASGoogle Scholar
• 17. Finberg JPM. Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease. J. Neural. Transm. 126(4), 433–448 (2019).
  MedlineGoogle Scholar
• 18. Marino BLB, de Souza LR, Sousa KPA et al. Parkinson's disease: a review from pathophysiology to treatment. Mini Rev. Med. Chem. 20(9), 754–767 (2020). • Illustrates the pathophysiology and treatment of Parkinson's disease.
  Medline CASGoogle Scholar
• 19. Jiang D-Q, Li M-X, Jiang L-L et al. Comparison of selegiline and levodopa combination therapy versus levodopa monotherapy in the treatment of Parkinson's disease: a meta-analysis. Aging Clin. Exp. Res. 32(5), 1–11 (2020).
  MedlineGoogle Scholar
• 20. Dashtipour K, Tafreshi AR, Pahwa R, Lyons KE. Extended-release amantadine for levodopa-induced dyskinesia. Exp. Rev. Neurother. 19(4), 293–299 (2019).
  Medline CASGoogle Scholar
• 21. Geldenhuys WJ, Van der Schyf CJ. Rationally designed multi-targeted agents against neurodegenerative diseases. Curr. Med. Chem. 20(13), 1662–1672 (2013).
  Medline CASGoogle Scholar
• 22. Wang Yali, Sun Yang, Guo Yueyan et al. Dual functional cholinesterase and MAO inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of homoisoflavonoid derivatives. J. Enzyme Inhib. Med. Chem. 31(3), 389–397 (2016).
  Medline CASGoogle Scholar
• 23. Matos MJ, Janeiro P, González Franco RM et al. Synthesis, pharmacological study and docking calculations of new benzo[f]coumarin derivatives as dual inhibitors of enzymatic systems involved in neurodegenerative diseases. Future Med. Chem. 6(4), 371–383 (2014).
  CASGoogle Scholar
• 24. Liu W, Lang M, Youdim MBH et al. Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer's disease. Neuropharmacology 109, 376–385 (2016).
  Medline CASGoogle Scholar
• 25. Yáñez M, Viña D. Dual inhibitors of monoamine oxidase and cholinesterase for the treatment of Alzheimer disease. Curr. Top. Med. Chem. 13(14), 1692–1706 (2013).
  Medline CASGoogle Scholar
• 26. Goyal M, Dhanjal JK, Goyal S. Development of dual inhibitors against Alzheimer's disease using fragment-based QSAR and molecular docking. Biomed. Res. Int. 2014, 979606 (2014).
  MedlineGoogle Scholar
• 27. Duarte Y, Fonseca A, Gutiérrez M et al. Novel coumarin-quinoline hybrids: design of multitarget compounds for Alzheimer's disease. ChemistrySelect 4, 551–558 (2019).
  CASGoogle Scholar
• 28. Ballard CG. Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. Eur. Neurol. 47(1), 64–70 (2002).
  Medline CASGoogle Scholar
• 29. Viayna E, Coquelle N, Cieslikiewicz-Bouet M et al. Discovery of a potent dual inhibitor of acetylcholinesterase and butyrylcholinesterase with antioxidant activity that alleviates Alzheimer-like pathology in old APP/PS1 mice. J. Med. Chem. 64(1), 812–839 (2021).
  Medline CASGoogle Scholar
• 30. Petzer JP, Castagnoli N, Schwarzschild MA et al. Dual-target-directed drugs that block monoamine oxidase B and adenosine A2A receptors for Parkinson's disease. Neurotherapeutics 6(1), 141–151 (2009).
  Medline CASGoogle Scholar
• 31. Jaiteh M, Zeifman A, Saarinen M et al. Docking screens for dual inhibitors of disparate drug targets for Parkinson's disease. J. Med. Chem. 61(12), 5269–5278 (2018).
  Medline CASGoogle Scholar
• 32. Nesi G, Sestito S Digiacomo M, Rapposelli S. Oxidative stress, mitochondrial abnormalities and proteins deposition: multitarget approaches in Alzheimer's disease. Curr. Top. Med. Chem. 17(27), 3062–3079 (2017).
  MedlineGoogle Scholar
• 33. Buendia I, Navarro E, Michalska P et al. New melatonin-cinnamate hybrids as multi-target drugs for neurodegenerative diseases: Nrf2-induction, antioxidant effect and neuroprotection. Future Med. Chem. 7(15), 1961–1969 (2015).
  CASGoogle Scholar
• 34. Weinreb O, Amit T, Bar-Am O, Youdim MB. Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer's disease treatment. Curr. Drug Targets 13(4), 483–94 (2012).
  Medline CASGoogle Scholar
• 35. Xie S-S, Liu J, Tang C et al. Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-β aggregation against Alzheimer's disease. Eur. J. Med. Chem. 202(15), 112475 (2020).
  Medline CASGoogle Scholar
• 36. Matos MJ, Herrera Ibatá DM, Uriarte E, Viña D. Coumarin-rasagiline hybrids as potent and selective hMAO-B inhibitors, antioxidants and neuroprotective agents. ChemMedChem 15, 532–538 (2020).
  Medline CASGoogle Scholar
• 37. Zagórska A, Jaromin A. Perspectives for new and more efficient multifunctional ligands for Alzheimer's disease therapy. Molecules 25(15), 3337 (2020).
  CASGoogle Scholar
• 38. Fernandez-Bachiller MI, Perez C, Monjas L, Rademann J, Rodriguez-Franco MI. New tacrine-4-oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and betaamyloid-reducing properties. J. Med. Chem. 55, 1303–1317 (2012).
  Medline CASGoogle Scholar
• 39. Di L, Kerns EH, Fan K, McConnell OJ, Carter GT. High throughput artificial membrane permeability assay for blood-brain barrier. Eur. J. Med. Chem. 38, 223–232 (2003).
  Medline CASGoogle Scholar
• 40. Iraji A, Khoshneviszadeh M, Firuzi O, Khoshneviszadeh M, Edraki N. Novel small molecule therapeutic agents for Alzheimer disease: focusing on BACE1 and multi-target directed ligands. Bioorg. Chem. 97, 103649 (2020). •• Extensive and complete overview of BACE1 inhibitors.
  Medline CASGoogle Scholar
• 41. Li SY, Wang XB, Xie SS et al. Multifunctional tacrine-flavonoid hybrids with cholinergic, beta-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 69, 632–646 (2013).
  Medline CASGoogle Scholar
• 42. Mesiti F, Chavarria D, Gaspar A, Alcaro S, Borges F. The chemistry toolbox of multitarget-directed ligands for Alzheimer's disease. Eur. J. Med. Chem. 181, 111572 (2019). •• Extensive and complete overview of the chemistry toolbox of multitarget ligands for Alzheimer's disease.
  Medline CASGoogle Scholar
• 43. Ismaili L, Refouvelet B, Benchekroun M et al. Multitarget compounds bearing tacrine- and donepezil-like structural and functional motifs for the potential treatment of Alzheimer's disease. Prog. Neurobiol. 151, 4–34 (2017).
  Medline CASGoogle Scholar
• 44. Wu WY, Dai YC, Li NG et al. Novel multitarget-directed tacrine derivatives as potential candidates for the treatment of Alzheimer's disease. J. Enzyme Inhib. Med. Chem. 32(1), 572–587 (2017).
  Medline CASGoogle Scholar
• 45. Catto M, Pisani L, Leonetti F et al. Design, synthesis and biological evaluation of coumarin alkylamines as potent and selective dual binding site inhibitors of acetylcholinesterase. Bioorg. Med. Chem. 21, 146–152 (2013).
  Medline CASGoogle Scholar
• 46. Wu MY, Esteban G, Brogi S et al. Donepezil-like multifunctional agents: design, synthesis, molecular modeling and biological evaluation. Eur. J. Med. Chem. 121, 864–879 (2016).
  Medline CASGoogle Scholar
• 47. Ferreira JPS, Albuquerque HMT, Cardoso SM, Silva AMS, Silva VLM. Dual-target compounds for Alzheimer's disease: natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR). Eur. J. Med. Chem. 221, 113492 (2021).
  Medline CASGoogle Scholar
• 48. Malafaia D, Albuquerque HMT, Silva AMS. Amyloid-β and tau aggregation dual-inhibitors: a synthetic and structure-activity relationship focused review. Eur. J. Med. Chem. 214, 113209 (2021).
  Medline CASGoogle Scholar
• 49. Benek O, Korabecny J, Soukup O. A perspective on multi-target drugs for Alzheimer's disease. Trends Pharmacol. Sci. 41(7), 434–445 (2020). •• Highlights the advantages and drawbacks of multitarget drugs for Alzheimer's disease.
  Medline CASGoogle Scholar