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Research Article

Design, synthesis and biological evaluation of novel indanones derivatives as potent acetylcholinesterase/monoamine oxidase B inhibitors

    Zhaoxin Hu

    Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    ,
    Shengnan Zhou

    State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    ,
    Junda Li

    State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    ,
    Xinnan Li

    State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    ,
    Yang Zhou

    State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    ,
    Zheying Zhu

    School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK

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    ,
    Jinyi Xu

    *Author for correspondence:

    E-mail Address: jinyixu@china.com

    State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    &
    Jie Liu

    **Author for correspondence:

    E-mail Address: cpu-jill@163.com

    Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing, 211198, People's Republic of China

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    Published Online:30 Oct 2023https://doi.org/10.4155/fmc-2023-0206

    Abstract

    Aim: Based on a multitarget design strategy, a series of novel indanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Results: These compounds exhibited significant inhibitory activities against acetylcholinesterase (AChE) and moderate inhibitory activities toward monoamine oxidase B (MAO-B). The optimal compound A1 possessed excellent dual AChE/MAO-B inhibition both in terms of potency (AChE: IC50 = 0.054 ± 0.004 μM; MAO-B: IC50 = 3.25 ± 0.20 μM), moderate inhibitory effects on self-mediated amyloid-β (Aβ) aggregation and antioxidant activity. In addition, compound A1 exhibited low neurotoxicity. More importantly, compound A1 showed significant cognitive and spatial memory improvements in the scopolamine-induced AD mouse model. Conclusion: All results suggest that compound A1 may become a promising lead of anti-AD drug for further development.

    Graphical abstract

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

    References

    • 1. Scheltens P, Blennow K, Breteler MMB et al. Alzheimer's disease. Lancet 388(10043), 505–517 (2016). • Discusses the challenging treatment of Alzheimer's disease.
      Medline CASGoogle Scholar
    • 2. Rajasekhar K, Govindaraju T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer's disease. RSC Adv. 8(42), 23780–23804 (2018).
      Medline CASGoogle Scholar
    • 3. Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8(6), 595–608 (2016).
      Medline CASGoogle Scholar
    • 4. Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71(4), 505–508 (2014).
      MedlineGoogle Scholar
    • 5. Lansdall CJ. An effective treatment for Alzheimer's disease must consider both amyloid and tau. Bioscience Horizons 7, hzu002 (2014).
      Google Scholar
    • 6. Barnham KJ, Bush AI. Biological metals and metal-targeting compounds in major neurodegenerative diseases. Chem. Soc. Rev. 43(19), 6727–6749 (2014).
      Medline CASGoogle Scholar
    • 7. Eckert A, Schmitt K, Götz J. Mitochondrial dysfunction – the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity. Alzheimers Res. Ther. 3(2), 15 (2011).
      Medline CASGoogle Scholar
    • 8. Zhang P, Xu S, Zhu Z, Xu J. Multi-target design strategies for the improved treatment of Alzheimer's disease. Eur. J. Med. Chem. 176, 228–247 (2019).
      Medline CASGoogle Scholar
    • 9. Li X, Li T, Zhang P et al. Discovery of novel hybrids containing clioquinol-1-benzyl-1,2,3,6-tetrahydropyridine as multi-target-directed ligands (MTDLs) against Alzheimer's disease. Eur. J. Med. Chem. 244, 114841 (2022).
      Medline CASGoogle Scholar
    • 10. Zotova E, Nicoll JA, Kalaria R, Holmes C, Boche D. Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimers Res. Ther. 2(1), 1 (2010).
      MedlineGoogle Scholar
    • 11. Perry VH, Holmes C. Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10(4), 217–224 (2014).
      Medline CASGoogle Scholar
    • 12. Steele JW, Fan E, Kelahmetoglu Y, Tian Y, Bustos V. Modulation of autophagy as a therapeutic target for Alzheimer's disease. Postdoc. J. 1(2), 21–34 (2013).
      MedlineGoogle Scholar
    • 13. Zare-shahabadi A, Masliah E, Johnson GVW, Rezaei N. Autophagy in Alzheimer's disease. Rev. Neurosci. 26(4), 385–395 (2015).
      MedlineGoogle Scholar
    • 14. Wiesner J, Kříž Z, Kuča K, Jun D, Koča J. Acetylcholinesterases – the structural similarities and differences. J. Enzyme Inhib. Med. Chem. 22(4), 417–424 (2007).
      Medline CASGoogle Scholar
    • 15. van Greunen DG, Johan van der Westhuizen C, Cordier W et al. Novel N-benzylpiperidine carboxamide derivatives as potential cholinesterase inhibitors for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 179, 680–693 (2019).
      Medline CASGoogle Scholar
    • 16. Yao H, Uras G, Zhang P et al. Discovery of novel tacrine-pyrimidone hybrids as potent dual AChE/GSK-3 inhibitors for the treatment of Alzheimer's disease. J. Med. Chem. 64(11), 7483–7506 (2021).
      Medline CASGoogle Scholar
    • 17. Vitek GE, Decourt B, Sabbagh MN. Lecanemab (BAN2401): an anti-beta-amyloid monoclonal antibody for the treatment of Alzheimer disease. Expert Opin. Investig. Drugs 32(2), 89–94 (2023).
      Medline CASGoogle Scholar
    • 18. Zhou B, Lu JG, Siddu A, Wernig M, Südhof TC. Synaptogenic effect of APP-Swedish mutation in familial Alzheimer's disease. Sci. Transl. Med. 14(667), eabn9380 (2022).
      Medline CASGoogle Scholar
    • 19. Kumar B, Sheetal S, Mantha AK, Kumar V. Recent developments on the structure–activity relationship studies of MAO inhibitors and their role in different neurological disorders. RSC Adv. 6(48), 42660–42683 (2016).
      CASGoogle Scholar
    • 20. Binda C, Newton-Vinson P, Hubálek F, Edmondson DE, Mattevi A. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat. Struct. Mol. Biol. 9(1), 22–26 (2002).
      CASGoogle Scholar
    • 21. De Colibus L, Li M, Binda C, Lustig A, Edmondson DE, Mattevi A. Three-dimensional structure of human monoamine oxidase A (MAO A): relation to the structures of rat MAO A and human MAO B. Proc. Natl Acad. Sci. USA 102(36), 12684–12689 (2005).
      MedlineGoogle Scholar
    • 22. Finberg JPM. Update on the pharmacology of selective inhibitors of MAO-A and MAO-B: focus on modulation of CNS monoamine neurotransmitter release. Pharmacol. Ther. 143(2), 133–152 (2014).
      Medline CASGoogle Scholar
    • 23. Pisani L, Catto M, Leonetti F et al. Targeting monoamine oxidases with multipotent ligands: an emerging strategy in the search of new drugs against neurodegenerative diseases. Curr. Med. Chem. 18(30), 4568–4587 (2011). •• Explains that monoamine oxidase B (MAO-B) inhibitors can be used to treat neurodegenerative diseases.
      Medline CASGoogle Scholar
    • 24. Emilsson L, Saetre P, Balciuniene J, Castensson A, Cairns N, Jazin EE. Increased monoamine oxidase messenger RNA expression levels in frontal cortex of Alzheimer's disease patients. Neurosci. Lett. 326(1), 56–60 (2002).
      Medline CASGoogle Scholar
    • 25. Chan HH, Tse MK, Kumar S, Zhuo L. A novel selective MAO-B inhibitor with neuroprotective and anti-Parkinsonian properties. Eur. J. Pharmacol. 818, 254–262 (2018).
      Medline CASGoogle Scholar
    • 26. Reis J, Fernandes C, Salem H et al. Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties. Eur. J. Med. Chem. 239, 114507 (2022).
      Medline CASGoogle Scholar
    • 27. Manzoor S, Hoda N. A comprehensive review of monoamine oxidase inhibitors as anti-Alzheimer's disease agents: a review. Eur. J. Med. Chem. 206, 112787 (2020). •• Explains that novel multitarget design strategies may be an effective treatment method for Alzheimer's disease.
      Medline CASGoogle Scholar
    • 28. Agis-Torres A, Sollhuber M, Fernandez M, Sanchez-Montero JM. Multi-target-directed ligands and other therapeutic strategies in the search of a real solution for Alzheimer's disease. Curr. Neuropharmacol. 12(1), 2–36 (2014).
      Medline CASGoogle Scholar
    • 29. Carradori S, Ortuso F, Petzer A et al. Design, synthesis and biochemical evaluation of novel multi-target inhibitors as potential anti-Parkinson agents. Eur. J. Med. Chem. 143, 1543–1552 (2018).
      Medline CASGoogle Scholar
    • 30. Kumar B, Kumar V, Prashar V et al. Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase. Eur. J. Med. Chem. 177, 221–234 (2019).
      Medline CASGoogle Scholar
    • 31. Xie S-S, Wang X, Jiang N et al. Multi-target tacrine-coumarin hybrids: cholinesterase and monoamine oxidase B inhibition properties against Alzheimer's disease. Eur. J. Med. Chem. 95, 153–165 (2015).
      Medline CASGoogle Scholar
    • 32. Sterling J, Herzig Y, Goren T et al. Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. J. Med. Chem. 45(24), 5260–5279 (2002). •• Elaborates on MAO-B inhibitors with indan-1-one structure as the backbone.
      Medline CASGoogle Scholar
    • 33. Mostert S, Petzer A, Petzer JP. Indanones as high-potency reversible inhibitors of monoamine oxidase. ChemMedChem 10(5), 862–873 (2015). •• Reports a new chromanone derivative C10, which is an acetylcholinesterase/MAO-B inhibitor.
      Medline CASGoogle Scholar
    • 34. Li X, Li T, Zhan F et al. Design, synthesis, and biological evaluation of novel chromanone derivatives as multifunctional agents for the treatment of Alzheimer's disease. ACS Chem. Neurosci. 13(23), 3488–3501 (2022).
      Medline CASGoogle Scholar
    • 35. Zhang H, Wang Y, Wang Y, Li X, Wang S, Wang Z. Recent advance on carbamate-based cholinesterase inhibitors as potential multifunctional agents against Alzheimer's disease. Eur. J. Med. Chem. 240, 114606 (2022).
      Medline CASGoogle Scholar
    • 36. Jiang N, Li S-Y, Xie S-S et al. Design, synthesis and evaluation of multifunctional salphen derivatives for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 87, 540–551 (2014).
      Medline CASGoogle Scholar
    • 37. Umar T, Shalini S, Raza MK et al. 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. 175, 2–19 (2019).
      Medline CASGoogle Scholar
    • 38. Jiang T, Sun Q, Chen S. Oxidative stress: a major pathogenesis and potential therapeutic target of antioxidative agents in Parkinson's disease and Alzheimer's disease. Prog. Neurobiol. 147, 1–19 (2016).
      Medline CASGoogle Scholar