Synthesis of 8-phenyl substituted 3-benzazecines with allene moiety, their thermal rearrangement and evaluation as acetylcholinesterase inhibitors

Abstract

Various 4′-R-substituted phenyl azacyclic allenes were synthesized in good yields, and their thermal transformations were studied. For the first time, the obtained rearrangement products—new N-bridged cyclopenta[a]indenes, and the corresponding parent allenes were evaluated as potential inhibitors of acetyl- and butyrylcholinesterase. Among the tested compounds, the allene derivative 2g proved to competitively inhibit human AChE with inhibition constant value (Ki) in the low micromolar range.

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References

  1. 1.

    Perscheid M, Schollmeyer D, Nubbemeyer U (2011) First synthesis of medium-sized ring allenyl lactams. Eur J Org Chem 27:5250–5253. https://doi.org/10.1002/ejoc.201100830

    CAS  Article  Google Scholar 

  2. 2.

    Voskressensky LG, Titov AA, Dzhankaziev MS, Borisova TN, Kobzev MS, Dorovatovskii PV, Khrustalev VN, Aksenov AV, Varlamov AV (2017) First synthesis of heterocyclic allenes-benzazecine derivatives. New J Chem 41:1902–1904. https://doi.org/10.1039/C6NJ03403A

    CAS  Article  Google Scholar 

  3. 3.

    Titov AA, Kobzev MS, Borisova TN, Listratova AV, Evenko TV, Varlamov AV, Voskressensky LG (2020) Facile methods for the synthesis of 8-ylidene-1,2,3,8-tetrahydrobenzazecines. Eur J Org Chem 20:3041–3049. https://doi.org/10.1002/ejoc.202000203

    CAS  Article  Google Scholar 

  4. 4.

    Titov AA, Kobzev MS, Borisova TN, Sorokina EA, Van der Eycken E, Varlamov AV, Voskressensky LG (2020) Unusual transformations of cyclic allenes with an enamine moiety into complex frameworks. Synlett 31:672–676. https://doi.org/10.1055/s-0039-1691586

    CAS  Article  Google Scholar 

  5. 5.

    Titov AA, Niso M, de Candia M, Kobzev MS, Varlamov AV, Borisova TN, Voskressensky LG, Colabufo NA, Cellamare S, Pisani L, Altomare CD (2019) 3-benzazecine-based cyclic allene derivatives as highly potent P-glycoprotein inhibitors overcoming doxorubicin multidrug resistance. Future Med Chem 11:2095–2106. https://doi.org/10.4155/fmc-2019-0037

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Taylor AM, Schreiber SL (2006) Enantioselective addition of terminal alkynes to isolated isoquinoline iminiums. Org Lett 8:143–146. https://doi.org/10.1021/ol0526165

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Capilla AS, Romero M, Pujol MD, Caignard DH, Renard P (2001) Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents. Tetrahedron 57:8297. https://doi.org/10.1016/S0040-4020(01)00826-2

    CAS  Article  Google Scholar 

  8. 8.

    Feng B, Doran AC, Di L, West MA, Osgood SM, Mancuso JY, Shaffer CL, Tremaine L, Liras JJ (2018) Prediction of human brain penetration of P-glycoprotein and breast cancer resistance protein substrates using in vitro transporter studies and animal models. Pharm Sci 107:2225–2235. https://doi.org/10.1016/j.xphs.2018.03.018

    CAS  Article  Google Scholar 

  9. 9.

    Waghray D, Zhang QJ (2018) Inhibit or evade multidrug resistance P-glycoprotein in cancer treatment. Med Chem 61:5108–5121. https://doi.org/10.1021/acs.jmedchem.7b01457

    CAS  Article  Google Scholar 

  10. 10.

    Unzeta M, Esteban G, Bolea I, Fogel WA, Ramsay RR, Youdim MBH, Tipton KF, Marco-Contelles J (2016) Multi-target directed donepezil-like ligands for Alzheimer’s disease. Front Neurosci 25:205. https://doi.org/10.3389/fnins.2016.00205

    Article  Google Scholar 

  11. 11.

    Rullo M, Catto M, Carrieri A, de Candia M, Altomare CD, Pisani L (2019) Chasing ChEs-MAO B multi-targeting 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones. Molecules 24:4507. https://doi.org/10.3390/molecules24244507

    CAS  Article  PubMed Central  Google Scholar 

  12. 12.

    Pisani L, De Palma A, Giangregorio N, Miniero DV, Pesce P, Nicolotti O, Campagna F, Altomare CD, Catto M (2017) Mannich base approach to 5-methoxyisatin 3-(4-isopropylphenyl)hydrazone: a water-soluble prodrug for a multitarget inhibition of cholinesterases, beta-amyloid fibrillization and oligomer-induced cytotoxicity. Eur J Pharm Sci 109:381–388. https://doi.org/10.1016/j.ejps.2017.08.004

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Purgatorio R, de Candia M, Catto M, Carrieri A, Pisani L, De Palma A, Toma A, Ivanova OA, Voskressensky LG, Altomare CD (2019) Investigating 1,2,3,4,5,6-hexahydroazepino[4,3-b]indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer’s disease. Eur J Med Chem 177:414–424. https://doi.org/10.1016/j.ejmech.2019.05.062

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Bolognino I, Giangregorio N, Pisani L, de Candia M, Purgatorio R, Tonazzi A, Altomare CD, Cellamare S, Catto M (2019) A prospective repurposing of dantrolene as a multitarget agent for Alzheimer’s disease. Molecules 24:4298. https://doi.org/10.3390/molecules24234298

    CAS  Article  PubMed Central  Google Scholar 

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Acknowledgements

The publication has been prepared with support of the Russian Science Foundation (project No. 18-73-10057).

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Correspondence to Alexander A. Titov.

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Kobzev, M.S., Titov, A.A., Alexandrova, E.V. et al. Synthesis of 8-phenyl substituted 3-benzazecines with allene moiety, their thermal rearrangement and evaluation as acetylcholinesterase inhibitors. Mol Divers (2021). https://doi.org/10.1007/s11030-021-10185-8

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Keywords

  • Azacyclic allenes
  • Acetylcholinesterase inhibitors
  • N-bridged cyclopenta[a]indenes