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An Integrated Computational Approaches for Designing of Potential Piperidine based Inhibitors of Alzheimer Disease by Targeting Cholinesterase and Monoamine Oxidases Isoenzymes

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Abstract

The study aimed to evaluate the potential of piperidine-based 2H chromen-2-one derivatives against targeted enzymes, i.e., cholinesterase’s and monoamine oxidase enzymes. The compounds were divided into three groups, i.e., 4a–m ((3,4-dimethyl-7-((1-methylpiperidin-4-yl)oxy)-2H-chromen-2-one derivatives), 5a–e (3,4-dimethyl-7-((1-methypipridin-3-yl)methoxy)-2H-chromen-2-one derivatives), and 7a–b (7-(3-(3,4-dihydroisoquinolin-2(1H)-yl)propoxy)-3,4-dimethyl-2H-chromen-2-one derivatives) with slight difference in the basic structure. The comprehensive computational investigations were conducted including density functional theories studies (DFTs), 2D-QSAR studies, molecular docking, and molecular dynamics simulations. The QSAR equation revealed that the activity of selected chromen-2-one-based piperidine derivatives is being affected by the six descriptors, i.e., Nitrogens Count, SdssCcount, SssOE-Index, T-2–2-7, ChiV6chain, and SssCH2E-Index. These descriptor values were further used for the preparation of chromen-2-one based piperidine derivatives. Based on this, 83 new derivatives were created from 7 selected parent compounds. The QSAR model predicted their IC50 values, with compound 4 k and 4kk as the most potent multi-targeted derivative. Molecular docking results exhibited these compounds as the best inhibitors; however, 4kk exhibited greater activity than the parent compounds. The results were further validated by molecular dynamic simulation studies along with the suitable physicochemical properties. These results prove to be an essential guide for the further design and development of new piperidine based chromen-2-one derivatives having better activity against neurodegenerative disorder.

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References

  1. Lau, A., et al. (2021). Alzheimer’s disease-related metabolic pattern in diverse forms of neurodegenerative diseases. Diagnostics, 11(11), 2023.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Atri, A. (2019). The Alzheimer’s disease clinical spectrum: Diagnosis and management. Medical Clinics, 103(2), 263–293.

    PubMed  Google Scholar 

  3. Perl, D. P. (2010). Neuropathology of Alzheimer’s disease. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine: A Journal of Translational and Personalized Medicine, 77(1), 32–42.

    Google Scholar 

  4. Huat, T. J., et al. (2019). Metal toxicity links to Alzheimer’s disease and neuroinflammation. Journal of Molecular Biology, 431(9), 1843–1868.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jakovljevic, M., et al. (2021). Aging and global health (pp. 73–102). Handbook of global health.

    Google Scholar 

  6. Jia, J., et al. (2018). The cost of Alzheimer’s disease in China and re-estimation of costs worldwide. Alzheimer’s & Dementia, 14(4), 483–491.

    Article  Google Scholar 

  7. Eckroat, T. J., Manross, D. L., & Cowan, S. C. (2020). Merged tacrine-based, multitarget-directed acetylcholinesterase inhibitors 2015–present: Synthesis and biological activity. International Journal of Molecular Sciences, 21(17), 5965.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Fitzgerald, P. J., et al. (2020). The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test. Translational Psychiatry, 10(1), 255.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Crews, F. T., et al. (2021). Loss of basal forebrain cholinergic neurons following adolescent binge ethanol exposure: Recovery with the cholinesterase inhibitor galantamine. Frontiers in Behavioral Neuroscience, 15, 652494.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Schneider, L. S. (2022). A critical review of cholinesterase inhibitors as a treatment modality in Alzheimer’s disease. Dialogues in clinical neuroscience, 2(2), 111–128.

    Article  Google Scholar 

  11. .Jha, A., & Singh, A. (2021). Cholinesterase inhibitors used for the management of Alzheimer’s disease: A review. Journal of Pharmaceutical Research International, 33(60A), 121–128.

    Google Scholar 

  12. Szökő, É., et al. (2018). Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline, in Parkinson’s disease. Journal of Neural Transmission, 125, 1735–1749.

    Article  PubMed  Google Scholar 

  13. Bortolami, M., et al. (2021). Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease–A patent review (2016–present). Expert Opinion on Therapeutic Patents, 31(5), 399–420.

    Article  PubMed  CAS  Google Scholar 

  14. Chen, Z.-R., et al. (2022). Role of cholinergic signaling in Alzheimer’s disease. Molecules, 27(6), 1816.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Yang, W., et al. (2020). Current and projected future economic burden of Parkinson’s disease in the US. npj Parkinson’s Disease, 6(1), 15.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Monzio Compagnoni, G., et al. (2020). The role of mitochondria in neurodegenerative diseases: The lesson from Alzheimer’s disease and Parkinson’s disease. Molecular neurobiology, 57, 2959–2980.

    Article  PubMed  CAS  Google Scholar 

  17. Cummings, J. (2021). The role of neuropsychiatric symptoms in research diagnostic criteria for neurodegenerative diseases. The American Journal of Geriatric Psychiatry, 29(4), 375–383.

    Article  PubMed  Google Scholar 

  18. Post, B., et al. (2020). Young onset Parkinson’s disease: A modern and tailored approach. Journal of Parkinson’s Disease, 10(s1), S29–S36.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Delavar, M. R., et al. (2018). Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson’s disease. Gene, 662, 54–65.

    Article  Google Scholar 

  20. Friedlander, A. H., et al. (2009). Parkinson disease: Systemic and orofacial manifestations, medical and dental management. The Journal of the American Dental Association, 140(6), 658–669.

    Article  PubMed  Google Scholar 

  21. Santin, Y., et al. (2020). Mitochondrial 4-HNE derived from MAO-A promotes mitoCa2+ overload in chronic postischemic cardiac remodeling. Cell Death & Differentiation, 27(6), 1907–1923.

    Article  CAS  Google Scholar 

  22. Pathania, A., Kumar, R., & Sandhir, R. (2021). Hydroxytyrosol as anti-parkinsonian molecule: Assessment using in-silico and MPTP-induced Parkinson’s disease model. Biomedicine & Pharmacotherapy, 139, 111525.

    Article  CAS  Google Scholar 

  23. Binde, C. D., et al. (2018). A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson’s disease. British Journal of Clinical Pharmacology, 84(9), 1917–1927.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Aksoz, B. E., & Aksoz, E. (2020). Vital role of monoamine oxidases and cholinesterases in central nervous system drug research: A sharp dissection of the pathophysiology. Combinatorial Chemistry & High Throughput Screening, 23(9), 877–886.

    Article  CAS  Google Scholar 

  25. Löscher, W., & Potschka, H. (2005). Drug resistance in brain diseases and the role of drug efflux transporters. Nature Reviews Neuroscience, 6(8), 591–602.

    Article  PubMed  Google Scholar 

  26. Grygorenko, O. O., Volochnyuk, D. M., & Vashchenko, B. V. (2021). Emerging building blocks for medicinal chemistry: Recent synthetic advances. European Journal of Organic Chemistry, 2021(47), 6478–6510.

    Article  CAS  Google Scholar 

  27. Haider, S., et al. (2014). Emerging pharmaceutical applications of piperidine, pyrrolidine and its derivatives. World Journal of Pharmaceutical Research, 3(7), 2277–7105.

    Google Scholar 

  28. Szczepańska, K., et al. (2021). Structural and molecular insight into piperazine and piperidine derivatives as histamine H3 and sigma-1 receptor antagonists with promising antinociceptive properties. ACS Chemical Neuroscience, 13(1), 1–15.

    Article  PubMed  Google Scholar 

  29. Nasab, N. H., et al. (2022). Coumarin-chalcones generated from 3-acetylcoumarin as a promising agent: Synthesis and pharmacological properties. ChemistrySelect, 7(11), e202200238.

    Article  CAS  Google Scholar 

  30. Pisani, L., et al. (2016). Exploring basic tail modifications of coumarin-based dual acetylcholinesterase-monoamine oxidase B inhibitors: Identification of water-soluble, brain-permeant neuroprotective multitarget agents. Journal of Medicinal Chemistry, 59(14), 6791–6806.

    Article  PubMed  CAS  Google Scholar 

  31. Heo, J. H., et al. (2020). Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg. Scientific Reports, 10(1), 1–11.

    Article  Google Scholar 

  32. Aljohani, F. S., et al. (2021). Structural inspection for novel Pd (II), VO (II), Zn (II) and Cr (III)-azomethine metal chelates: DNA interaction, biological screening and theoretical treatments. Journal of Molecular Structure, 1246, 131139.

    Article  CAS  Google Scholar 

  33. Ejaz, S. A., et al. (2022). Identification of N-(4-acetyl-4, 5-dihydro-5-(7, 8, 9-substituted-tetrazolo [1, 5-a]-quinolin-4-yl)-1, 3, 4-thiadiazol-2-yl) acetamide derivatives as potential caspase-3 inhibitors via detailed computational investigations. Structural Chemistry, 34(2), 1–14.

    Google Scholar 

  34. Mahesar, P. A., et al. (2023). Potential role of hydrazinyl 1, 2, 4-triazoles derivatives as acetylcholinesterase inhibitors: Synthesis, biological evaluation, kinetics mechanism and molecular docking and simulation studies. Chemical Papers, 77(1), 1–13.

    Google Scholar 

  35. Nachon, F., et al. (2013). Crystal structures of human cholinesterases in complex with huprine W and tacrine: Elements of specificity for anti-Alzheimer’s drugs targeting acetyl-and butyryl-cholinesterase. Biochemical Journal, 453(3), 393–399.

    Article  PubMed  CAS  Google Scholar 

  36. Ahmed, M., et al. (2006). Inhibition of two different cholinesterases by tacrine. Chemico-Biological Interactions, 162(2), 165–171.

    Article  PubMed  CAS  Google Scholar 

  37. Son, S. (2002). Crystal structure of human monoamine oxidase A. Neuroscience, 114(4), 825–835.

    Google Scholar 

  38. Binda, C., et al. (2007). Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: Safinamide and coumarin analogs. Journal of Medicinal Chemistry, 50(23), 5848–5852.

    Article  PubMed  CAS  Google Scholar 

  39. Aziz, M., et al. (2022). Identification of potent inhibitors of NEK7 protein using a comprehensive computational approach. Scientific Reports, 12(1), 6404.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ejaz, S. A., et al. (2022). In silico prospects and therapeutic applications of ouabagenin and hydroxylated corticosteroid analogues in the treatment of lung cancer. Applied Biochemistry and Biotechnology, 194(12), 6106–6125.

    Article  PubMed  CAS  Google Scholar 

  41. Aziz, M., et al. (2022). Deep learning and structure-based virtual screening for drug discovery against NEK7: A novel target for the treatment of cancer. Molecules, 27(13), 4098.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ejaz, S. A., et al. (2022). 4-Phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: DFTs, 3D-QSAR, ADMET, and molecular dynamics simulation. Neurodegenerative Diseases, 22(3–4), 1–17.

    Google Scholar 

  43. Ahmed, A., et al. (2022). Design, synthesis, kinetic analysis and pharmacophore-directed discovery of 3-ethylaniline hybrid imino-thiazolidinone as potential inhibitor of carbonic anhydrase II: An emerging biological target for treatment of cancer. Biomolecules, 12(11), 1696.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Khan, I., et al. (2015). Investigation of quinoline-4-carboxylic acid as a highly potent scaffold for the development of alkaline phosphatase inhibitors: Synthesis, SAR analysis and molecular modelling studies. RSC advances, 5(79), 64404–64413.

    Article  CAS  Google Scholar 

  45. Channar, S. A., et al. (2022). Exploring thiazole-linked thioureas using alkaline phosphatase assay, biochemical evaluation, computational analysis and structure–activity relationship (SAR) studies. Medicinal Chemistry Research, 31(10), 1792–1802.

    Article  CAS  Google Scholar 

  46. Hansson, T., Oostenbrink, C., & van Gunsteren, W. (2002). Molecular dynamics simulations. Current opinion in structural biology, 12(2), 190–196.

    Article  PubMed  CAS  Google Scholar 

  47. Deb, S., & Reeves, A. A. (2021). Simulation of remdesivir pharmacokinetics and its drug interactions. Journal of Pharmacy and Pharmaceutical Sciences., 24, 277–291.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We acknowledge Al Ain University for providing facilities and resources to rum the in silico simulation using Gastro plus Software.

Funding

Arab Emirates University for awarding Research Start-up grant No.: 700032854.

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Authors and Affiliations

  1. College of Pharmacy, Al Ain University, Al Ain Campus, 64141, Al Ain, United Arab Emirates

    Muhammad Sarfraz & Mosab Arafat

  2. AU Health and Biomedical Research Center, Al Ain University, Abu Dhabi, United Arab Emirates

    Muhammad Sarfraz

  3. Baqai Medical University Karachi, Karachi, 75340, Pakistan

    Muhammad Khurrum Ibrahim

  4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan

    Syeda Abida Ejaz, Hafiz Muhammad Attaullah & Mubashir Aziz

  5. Faculty of Medicine and Allied Health Sciences, University College of Conventional Medicine, The Islamia University of Bahawalpur, Bahawalpur, Pakistan

    Tahira Shamim

  6. Department of Physics, Faculty of Science and Humanities, Shaqra University, Ad-Dawadimi 11911, P.O.Box 1040, Shaqra, Saudi Arabia

    Muawya Elhadi

  7. Institute of Zoology, Bahaudin Zakariya University Multan, Multan, 60800, Pakistan

    Tahira Ruby & Hafiz Kashif Mahmood

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Contributions

M.S.: methodology, investigations. M.K.I.: methodology, experimental material design, investigations. S.A.E..: conceptualization, methodology, supervision, investigation, writing review and editing. M.A.: methodology, experimental material design, investigations. H. M.A.: methodology, investigations, writing review and editing. M.A.: investigation, writing-review and editing. T.S.: methodology, formal analysis. T.R.: investigation, writing-review and editing. H.K.M.: investigation, writing-review and editing. M.E.: revision and resources. All authors read and approved the final manuscript.

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Correspondence to Muhammad Sarfraz or Syeda Abida Ejaz.

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Sarfraz, M., Ibrahim, M.K., Ejaz, S.A. et al. An Integrated Computational Approaches for Designing of Potential Piperidine based Inhibitors of Alzheimer Disease by Targeting Cholinesterase and Monoamine Oxidases Isoenzymes. Appl Biochem Biotechnol (2024). https://doi.org/10.1007/s12010-023-04815-0

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