Skip to content
2000
  1. Home
  2. A-Z Publications
  3. CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders)
  4. Fast Track Articles
  5. Fast Track Article
image of In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer’s Disease

Abstract

Background

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge.

Methods

Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives () to assess their possible AChE inhibiting ability using docking into the active sites.

Results

The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives () was explored docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives.

Conclusion

The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives () exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnsnddt/10.2174/0118715273315412241009092249
2024-10-25
2025-01-18

  • From This Site

    /content/journals/cnsnddt/10.2174/0118715273315412241009092249
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Unzeta M. Esteban G. Bolea I. Fogel W.A. Ramsay R.R. Youdim M.B.H. Tipton K.F. Marco-Contelles J. Multi-target directed donepezil-like ligands for alzheimer’s disease. Front. Neurosci. 2016 10 205 10.3389/fnins.2016.00205 27252617
    [Google Scholar]
  2. Karimi Askarani H. Iraji A. Rastegari A. Abbas Bukhari S.N. Firuzi O. Akbarzadeh T. Saeedi M. Design and synthesis of multi-target directed 1,2,3-triazole-dimethylaminoacryloyl-chromenone derivatives with potential use in Alzheimer’s disease. BMC Chem. 2020 14 1 64 10.1186/s13065‑020‑00715‑0 33134975
    [Google Scholar]
  3. Sharma P. Srivastava P. Seth A. Tripathi P.N. Banerjee A.G. Shrivastava S.K. Comprehensive review of mechanisms of pathogenesis involved in Alzheimer’s disease and potential therapeutic strategies. Prog. Neurobiol. 2019 174 53 89 10.1016/j.pneurobio.2018.12.006 30599179
    [Google Scholar]
  4. Panpalli Ates M. Karaman Y. Guntekin S. Ergun M.A. Analysis of genetics and risk factors of Alzheimer’s disease. Neuroscience 2016 325 325 124 131 10.1016/j.neuroscience.2016.03.051 27026590
    [Google Scholar]
  5. 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. 2020 97 103649 10.1016/j.bioorg.2020.103649 32101780
    [Google Scholar]
  6. Apostolova L.G. Alzheimer disease. Continuum 2016 22 2, Dementia 419 434 10.1212/CON.0000000000000307 27042902
    [Google Scholar]
  7. Hung S.Y. Fu W.M. Drug candidates in clinical trials for Alzheimer’s disease. J. Biomed. Sci. 2017 24 1 47 10.1186/s12929‑017‑0355‑7 28720101
    [Google Scholar]
  8. Pike K.E. Savage G. Villemagne V.L. Ng S. Moss S.A. Maruff P. Mathis C.A. Klunk W.E. Masters C.L. Rowe C.C. -amyloid imaging and memory in non-demented individuals: Evidence for preclinical Alzheimer’s disease. Brain 2007 130 11 2837 2844 10.1093/brain/awm238 17928318
    [Google Scholar]
  9. Pithadia A.S. Lim M.H. Metal-associated amyloid-β species in Alzheimer’s disease. Curr. Opin. Chem. Biol. 2012 16 1-2 67 73 10.1016/j.cbpa.2012.01.016 22366383
    [Google Scholar]
  10. Martinez A. Castro A. Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs 2006 15 1 1 12 10.1517/13543784.15.1.1 16370929
    [Google Scholar]
  11. Hampel H. Vergallo A. Aguilar L.F. Benda N. Broich K. Cuello A.C. Cummings J. Dubois B. Federoff H.J. Fiandaca M. Genthon R. Haberkamp M. Karran E. Mapstone M. Perry G. Schneider L.S. Welikovitch L.A. Woodcock J. Baldacci F. Lista S. Alzheimer Precision Medicine Initiative (APMI) Precision pharmacology for Alzheimer’s disease. Pharmacol. Res. 2018 130 331 365 10.1016/j.phrs.2018.02.014 29458203
    [Google Scholar]
  12. Wang X.C. Xu Y.M. Li H.Y. Wu C.Y. Xu T.T. Luo N.C. Zhang S.J. Wang Q. Quan S.J. Jiao-tai-wan improves cognitive dysfunctions through cholinergic pathway in scopolamine-treated mice. BioMed Res. Int. 2018 2018 1 16 10.1155/2018/3538763 30050927
    [Google Scholar]
  13. Mohamed T. Rao P.P.N. 2,4-Disubstituted quinazolines as amyloid-β aggregation inhibitors with dual cholinesterase inhibition and antioxidant properties: Development and structure-activity relationship (SAR) studies. Eur. J. Med. Chem. 2017 126 823 843 10.1016/j.ejmech.2016.12.005 27951490
    [Google Scholar]
  14. Gill S.S. Anderson G.M. Fischer H.D. Bell C.M. Li P. Normand S.L.T. Rochon P.A. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch. Intern. Med. 2009 169 9 867 873 10.1001/archinternmed.2009.43 19433698
    [Google Scholar]
  15. Ram V.J. Sethi A. Nath M. Pratap R. The Chemistry of Heterocycles: Chemistry of Six to Eight Membered N, O, S, P and Se Heterocycles. Elsevier 2019
    [Google Scholar]
  16. Decker M. Krauth F. Lehmann J. Novel tricyclic quinazolinimines and related tetracyclic nitrogen bridgehead compounds as cholinesterase inhibitors with selectivity towards butyrylcholinesterase. Bioorg. Med. Chem. 2006 14 6 1966 1977 10.1016/j.bmc.2005.10.044 16289855
    [Google Scholar]
  17. Seo H.N. Choi J.Y. Choe Y.J. Kim Y. Rhim H. Lee S.H. Kim J. Joo D.J. Lee J.Y. Discovery of potent T-type calcium channel blocker. Bioorg. Med. Chem. Lett. 2007 17 21 5740 5743 10.1016/j.bmcl.2007.08.070 17869104
    [Google Scholar]
  18. Kang H.B. Rim H.K. Park J.Y. Choi H.W. Choi D.L. Seo J.H. Chung K.S. Huh G. Kim J. Choo D.J. Lee K.T. Lee J.Y. In vivo evaluation of oral anti-tumoral effect of 3,4-dihydroquinazoline derivative on solid tumor. Bioorg. Med. Chem. Lett. 2012 22 2 1198 1201 10.1016/j.bmcl.2011.11.083 22177784
    [Google Scholar]
  19. Darras F.H. Wehle S. Huang G. Sotriffer C.A. Decker M. Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with ‘inverted’ binding mode. Bioorg. Med. Chem. 2014 22 17 4867 4881 10.1016/j.bmc.2014.06.045 25047936
    [Google Scholar]
  20. Darras F.H. Kling B. Sawatzky E. Heilmann J. Decker M. Cyclic acyl guanidines bearing carbamate moieties allow potent and dirigible cholinesterase inhibition of either acetyl- or butyrylcholinesterase. Bioorg. Med. Chem. 2014 22 17 5020 5034 10.1016/j.bmc.2014.06.010 25059502
    [Google Scholar]
  21. Lazo-Porras M. Ortiz-Soriano V. Moscoso-Porras M. Runzer-Colmenares F.M. Málaga G. Jaime Miranda J. Cognitive impairment and hypertension in older adults living in extreme poverty: A cross-sectional study in Peru. BMC Geriatr. 2017 17 1 250 10.1186/s12877‑017‑0628‑8 29073885
    [Google Scholar]
  22. Naderali E.K. Ratcliffe S.H. Dale M.C. Obesity and Alzheimer’s disease: A link between body weight and cognitive function in old age. Am. J. Alzheimers Dis. Other Demen. 2009 24 6 445 449 10.1177/1533317509348208 19801534
    [Google Scholar]
  23. Mendiola-Precoma J. Berumen L.C. Padilla K. Garcia-Alcocer G. Therapies for prevention and treatment of alzheimer’s disease. BioMed Res. Int. 2016 2016 1 17 10.1155/2016/2589276 27547756
    [Google Scholar]
  24. Tariq S. Barber P.A. Dementia risk and prevention by targeting modifiable vascular risk factors. J. Neurochem. 2018 144 5 565 581 10.1111/jnc.14132 28734089
    [Google Scholar]
  25. Kivimäki M. Singh-Manoux A. Prevention of dementia by targeting risk factors. Lancet 2018 391 10130 1574 1575 10.1016/S0140‑6736(18)30578‑6 29695343
    [Google Scholar]
  26. Benny A. Thomas J. Essential oils as treatment strategy for alzheimerʼs disease: Current and future perspectives. Planta Med. 2019 85 3 239 248 10.1055/a‑0758‑0188 30360002
    [Google Scholar]
  27. Douchamps V. Mathis C. A second wind for the cholinergic system in Alzheimer’s therapy. Behav. Pharmacol. 2017 28 2 and 3 112 123 10.1097/FBP.0000000000000300 28240674
    [Google Scholar]
  28. Hampel H. Mesulam M.M. Cuello A.C. Farlow M.R. Giacobini E. Grossberg G.T. Khachaturian A.S. Vergallo A. Cavedo E. Snyder P.J. Khachaturian Z.S. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain 2018 141 7 1917 1933 10.1093/brain/awy132 29850777
    [Google Scholar]
  29. Cokugras A.N. Butyrylcholinesterase: Structure and physiological importance. Turk. J. Biochem 2003 28 54 61
    [Google Scholar]
  30. Bartus R.T. Dean R.L. III Beer B. Lippa A.S. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982 217 4558 408 414 10.1126/science.7046051 7046051
    [Google Scholar]
  31. Pinho B.R. Ferreres F. Valentão P. Andrade P.B. Nature as a source of metabolites with cholinesterase-inhibitory activity: An approach to Alzheimer’s disease treatment. J. Pharm. Pharmacol. 2013 65 12 1681 1700 10.1111/jphp.12081 24236980
    [Google Scholar]
  32. Ajani O.O. Aderohunmu D.V. Umeokoro E.N. Olomieja A.O. Quinazoline pharmacophore in therapeutic medicine. Bangladesh J. Pharmacol. 2016 11 3 716 733 10.3329/bjp.v11i3.25731
    [Google Scholar]
  33. Anwar M.M. Kamel M.M. Zaghary W.A. Al-Wabli R.I. Synthetic approaches and potential bioactivity of different functionalized quinazoline and quinazolinone scaffolds. Egypt. Pharm. J. 2016 15 3 98 131 10.4103/1687‑4315.197580
    [Google Scholar]
  34. Li Z. Wang B. Hou J.Q. Huang S.L. Ou T.M. Tan J.H. An L.K. Li D. Gu L.Q. Huang Z.S. 2-(2-indolyl-)-4(3 H )-quinazolines derivates as new inhibitors of AChE: design, synthesis, biological evaluation and molecular modelling. J. Enzyme Inhib. Med. Chem. 2013 28 3 583 592 10.3109/14756366.2012.663363 22380775
    [Google Scholar]
  35. Mohamed T. Mann M.K. Rao P.P.N. Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer’s disease. RSC Advances 2017 7 36 22360 22368 10.1039/C7RA02889J
    [Google Scholar]
  36. Zhao D. Wang T. Li J.X. Metal-free oxidative synthesis of quinazolinones via dual amination of sp 3 C–H bonds. Chem. Commun. 2014 50 49 6471 6474 10.1039/C4CC02648A 24816567
    [Google Scholar]
  37. Abualassal Q. Abudayeh Z. Husein-Al-Ali S.H. Synthesis of a spiro quinazoline compound as potential drug useful in the treatment of Alzheimer’s disease. Pharmakeftiki 2019 2 31 60 68
    [Google Scholar]
  38. AIKharaz F. Rational design and synthesis of quinazoline derivatives. İstanbul. J. Pharm. 2021 51 1 50 58
    [Google Scholar]
  39. Alsuhaimat R.A. Abualassal Q. Abudayeh Z.H. Ebad S.S. Albohye A. Synthesis and docking studies of a novel tetrahydroquinazoline derivative as promising scaffold for acetylcholine esterase inhibition. Egypt. J. Chem. 2020 63 12 4797 4804
    [Google Scholar]
  40. Yusuf M. Khan S.A. Assessment of ADME and in silico characteristics of natural-drugs from turmeric to evaluate significant COX2 inhibition. Biointerface Res. Appl. Chem. 2023 13 1 1 23
    [Google Scholar]
  41. Liu Y. Grimm M. Dai W. Hou M. Xiao Z.X. Cao Y. CB-Dock: A web server for cavity detection-guided protein–ligand blind docking. Acta Pharmacol. Sin. 2020 41 1 138 144 10.1038/s41401‑019‑0228‑6 31263275
    [Google Scholar]
  42. Nickel J. Gohlke B.O. Erehman J. Banerjee P. Rong W.W. Goede A. Dunkel M. Preissner R. SuperPred: Update on drug classification and target prediction. Nucleic Acids Res. 2014 42 W1 W26 W31 10.1093/nar/gku477 24878925
    [Google Scholar]
  43. Almehmadi M.M. Halawi M. Kamal M. Yusuf M. Chawla U. Asif M. Antimycobacterial activity of some new pyridinylpyridazine derivatives. Lat. Am. J. Pharm. 2022 41 7 1428 1432
    [Google Scholar]
  44. Dubois B. Epelbaum S. Nyasse F. Bakardjian H. Gagliardi G. Uspenskaya O. Houot M. Lista S. Cacciamani F. Potier M.C. Bertrand A. Lamari F. Benali H. Mangin J.F. Colliot O. Genthon R. Habert M.O. Hampel H. Audrain C. Auffret A. Baldacci F. Benakki I. Bertin H. Boukadida L. Cavedo E. Chiesa P. Dauphinot L. Dos Santos A. Dubois M. Durrleman S. Fontaine G. Genin A. Glasman P. Jungalee N. Kas A. Kilani M. La Corte V. Lehericy S. Letondor C. Levy M. Lowrey M. Ly J. Makiese O. Metzinger C. Michon A. Mochel F. Poisson C. Ratovohery S. Revillon M. Rojkova K. Roy P. Santos-Andrade K. Schindler R. Seux L. Simon V. Sole M. Tandetnik C. Teichmann M. Thiebaut de Shotten M. Younsi N. INSIGHT-preAD study group Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer’s disease (INSIGHT-preAD): A longitudinal observational study. Lancet Neurol. 2018 17 4 335 346 10.1016/S1474‑4422(18)30029‑2 29500152
    [Google Scholar]
  45. Mesulam M.M. Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer’s disease. J. Comp. Neurol. 2013 521 18 4124 4144 10.1002/cne.23415 23852922
    [Google Scholar]
  46. Massoud F. Gauthier S. Update on the pharmacological treatment of Alzheimer’s disease. Curr. Neuropharmacol. 2010 8 1 69 80 10.2174/157015910790909520 20808547
    [Google Scholar]
  47. Holzgrabe U. Kapková P. Alptüzün V. Scheiber J. Kugelmann E. Targeting acetylcholinesterase to treat neurodegeneration. Expert Opin. Ther. Targets 2007 11 2 161 179 10.1517/14728222.11.2.161 17227232
    [Google Scholar]
  48. Ballard C. Gauthier S. Corbett A. Brayne C. Aarsland D. Jones E. Alzheimer’s disease. Lancet 2011 377 9770 1019 1031 10.1016/S0140‑6736(10)61349‑9 21371747
    [Google Scholar]
  49. Pouramiri B. Abbasi M. Hadadianpour E. Design, green synthesis and in silico studies of new substituted naphtho[1,2‐e][1,3]oxazines as potential acetylcholinesterase inhibitors. Chem. Biodivers. 2024 e202401005 10.1002/cbdv.202401005 38923807
    [Google Scholar]
  50. Pouramiri B. Rashidi M. Lotfi S. Mohammadi M. Rabiei K. Biological evaluation of anti‐cholinesterase activity, in silico molecular docking studies, and DFT calculations of green synthesized thiadiazolo[3,2‐ a ]pyrimidine derivatives. Chem. Biodivers. 2023 20 11 e202301193 10.1002/cbdv.202301193 37869899
    [Google Scholar]
  51. Hadadianpour E. Pouramiri B. Facile, efficient and one-pot access to diverse new functionalized aminoalkyl and amidoalkyl naphthol scaffolds via green multicomponent reaction using triethylammonium hydrogen sulfate ([Et3NH][HSO4]) as an acidic ionic liquid under solvent-free conditions. Mol. Divers. 2020 24 1 241 252 10.1007/s11030‑019‑09945‑4 30953294
    [Google Scholar]
  52. Zheng Y. Tice C.M. Singh S.B. The use of spirocyclic scaffolds in drug discovery. Bioorg. Med. Chem. Lett. 2014 24 16 3673 3682 10.1016/j.bmcl.2014.06.081 25052427
    [Google Scholar]
  53. Ishola O. Ogunbowale A. Islam M.M. Hadadianpour E. Saman M. Adetuyi O. Georgieva E. Abstract 1073 Production and reconstitution in lipid nanoparticles of an engineered chimera construct of the Mtb EfpA drug exporter with apolipoprotein. J. Biol. Chem. 2024 300 3 106328 10.1016/j.jbc.2024.106328
    [Google Scholar]
  54. Asif M. Yusuf M. Almehmadi M. Alsaiari A.A. Allahyani M. Aljuaid A. Alsharif A. Towards antiviral potential of biomolecules derived from adhatod avasica as competent natural molecules to treat covid-19 virus variant. Lett. Org. Chem. 2024 21 5 466 477 10.2174/0115701786263427231123103651
    [Google Scholar]
  55. Yusuf M. Insights into the in-silico research: Current scenario, advantages, limits, and future perspectives. Life Insilico 2024 1 1 13 25
    [Google Scholar]
  56. Mariki A.A. Anaeigoudari A. Zahedifar M. Pouramiri B. Design, green synthesis, and biological evaluation of new substituted tetrahydropyrimidine derivatives as acetylcholinesterase inhibitors. PAHs 2021 42 8 5231 5241 10.1080/10406638.2021.1933102
    [Google Scholar]
  57. Yusuf M. Pal S. Shahid M. Asif M. Khan S.A. Tyagi R. Docking and ADMET study of arturmerone: Emerging scaffold for acetylcholine esterase inhibition and antidiabetic target. J. Appl. Organometallic Chem 2023 3 1 1 11
    [Google Scholar]
  58. Yusuf M. Rani S. Chawla U. Baindara P. Siddique S.A. Nirala K. Asif M. Modern perspectives on adiponectin: Targeting obesity, diabetes, and cancer together using herbal products. Biointerface Res. Appl. Chem. 2022 13 2 1 16
    [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273315412241009092249
Loading
In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer’s Disease
Bentham Science Publishers ; https://doi.org/10.2174/0118715273315412241009092249
/content/journals/cnsnddt/10.2174/0118715273315412241009092249
/content/journals/cnsnddt/10.2174/0118715273315412241009092249
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
Keywords: Quinazoline derivatives ; in-silico study ; Alzheimer’s disease ; molecular docking ; AChE inhibitors

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