Features of Conjugation of Ipidacrine Chloroalkylamides with 5-Acetyl-3-(Trifluoromethyl)Pyrazole and Its Derivatives. Study of Biological Activity

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

An approach to the preparation of ipidacrine conjugates with trifluoromethyl pyrazoles containing acetyl, hydrazone or oxime groups as functional substituents has been investigated. The alkylation of 5-acetyl-3-(trifluoromethyl)pyrazole with 2-chloroacetamide of ipidacrine proceeds non-regioselectively on the nitrogen atoms of the pyrazole ring, giving a mixture of 3-/5-CF3-regioisomeric products. The introduction of a hydrazone/oxime substituent into the structure of CF3-pyrazoles leads to the preferential formation of 3-CF3-regioisomeric conjugates. In alkylation reactions, preservation of the arylhydrazone substituent in pyrazolyl-containing ipidacrines is observed, whereas the oxime group undergoes hydrolysis to the acetyl function. Conjugation of 5-(1-hydroxizimylidenethyl)pyrazole with 3-chloropropanamide of ipidacrine was accompanied by partial reduction of the hydrazone substituent. 4-Chlorobutanamide of ipidacrine in MeCN did not react with pyrazoles, and upon heating in DMF 5-(1-hydroxizimylidenethyl)pyrazole underwent transamination to form symmetric ketazine. The conjugate with the N-propanamide spacer showed moderate selective inhibitory activity towards butyrylcholinesterase (IC50 = 14.5 ± 0.8 μM) and towards self-aggregation of β-amyloid (1–42). The introduction of an aryl substituent into the hydrazone fragment led to an increase in the antioxidant activity of pyrazoles and to the appearance of significant antioxidant properties of the conjugates in the ABTS (TEAC = 0.47–0.56) and FRAP (0.44–0.55 TE) tests.

About the authors

O. G. Khudina

I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences

Yekaterinburg, Russia

D. N. Bazhin

I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences; Ural Federal University named after the first President of Russia B.N. Yeltsin

Yekaterinburg, Russia; Yekaterinburg, Russia

G. F. Makhaeva

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences

Chernogolovka, Russia

Y. V. Burgart

I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences

Yekaterinburg, Russia

N. V. Kovaleva

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences

Chernogolovka, Russia

N. P. Boltneva

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences

Chernogolovka, Russia

E. V. Rudakova

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences

Chernogolovka, Russia

T. S. Skornjakova

Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences

Chernogolovka, Russia

V. I. Saloutin

I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences

Email: saloutin@ios.uran.ru
Yekaterinburg, Russia

References

  1. Лаврецкая Ф., Упадышева А.В., Григорьева Н.Д., Суханова С.А., Тимофеева А.К., Пенке И.X., Буров Ю.В., Робакидзе Т.Н. Материалы Второй Российской конференции “Болезнь Альцгеймера и старение: от нейробиологии к терапии”. Ред. С.И. Гаврилова. 18–20 октября, 1999.
  2. Ismaili L., Refouvelet B., Benchekroun M., Brogi S., Brindisi M., Gemma S., Campiani G., Filipic S., Agbaba D., Esteban G., Unzeta M., Nikolic K., Butini S., Marco-Contelles J. Prog. Neurobiol. 2017, 151, 4–34. https://doi.org/10.1016/j.pneurobio.2015.12.003
  3. Albertini C., Salerno A., de Sena Murteira Pinheiro P., Bolognesi M.L. Med. Res. Rev. 2021, 41, 2606–2633. https://doi.org/10.1002/med.21699
  4. Jana A., Bhattacharjee A., Das S.S., Srivastava A., Choudhury A., Bhattacharjee R., De S., Perveen A., Iqbal D., Gupta P.K., Jha S.K., Ojha S., Singh S.K., Ruokolainen J., Jha N.K., Kesari K.K., Ashraf G.M. Mol. Neurobiol. 2022, 59, 3512–3528. https://doi.org/10.1007/s12035-022-02779-6
  5. Mezeiova E., Prchal L., Hrabinova M., Muckova L., Pulkrabkova L., Soukup O., Misiachna A., Janou-sek J., Fibigar J., Kucera T., Horak M., Makhaeva G.F., Korabecny J. Biomed. Pharmacother. 2024, 173, 116399. https://doi.org/10.1016/j.biopha.2024.116399
  6. Alzheimer´s Association Report. Alzheimer’s Dementia. 2022, 18, 700–789. https://doi.org/10.1002/alz.12638
  7. Бачурин С.О. Журн. неврологии и психиатрии им. С.С. Корсакова. 2016, 116, 77–87. https://doi.org/10.17116/jnevro20161168177-87
  8. Makhaeva G.F., Lushchekina S.V., Kovaleva N.V., Astakhova T.Y., Boltneva N.P., Rudakova E.V., Serebryakova O.G., Proshin A.N., Serkov I.V., Trofimova T.P., Tafeenko V.A., Radchenko E.V., Palyulin V.A., Fisenko V.P., Korábečný J., Soukup O., Richardson R.J. Bioorg. Chem. 2021, 112, 104974. https://doi.org/10.1016/j.bioorg.2021.104974
  9. Khudina O.G., Grishchenko M.V., Makhaeva G.F., Burgart Y.V., Boltneva N.P., Goryaeva M.V., Kovaleva N.V., Rudakova E.V., Bachurin S.O., Saloutin V.I. Russ. Chem. Bull. 2024, 73, 1755–1765. https://doi.org/10.1007/s11172-024-4293-8
  10. Khudina O.G., Grishchenko M.V., Makhaeva G.F., Kovaleva N.V., Boltneva N.P., Rudakova E.V., Lushchekina S.V., Shchegolkov E.V., Borisevich S.S., Burgart Y.V., Saloutin V.I., Charushin V.N. Arch. Pharm. 2023, e2300447. https://doi.org/10.1002/ardp.202300447
  11. Grishchenko M.V., Khudina O.G., Makhaeva G.F., Burgart Y.V., Kovaleva N.V., Rudakova E.V., Boltneva N.P., Ulitko M.V., Saloutin V.I., Charushin V.N. Russ. Chem. Bull. 2024, 73, 3399–3409. https://doi.org/10.1007/s11172-024-4457-6
  12. Huang W. J., Zhang X., Chen W. W. Biomed. Rep. 2016, 4, 519–522. https://doi.org/10.3892/br.2016.630
  13. Silva V.L.M., Elguero J., Silva A.M.S. Eur. J. Med. Chem. 2018, 156, 394–429. https://doi.org/10.1016/j.ejmech.2018.07.007
  14. Zhao Z., Dai X., Li C., Wang X., Tian J., Feng Y., Xie J., Ma C., Nie Z., Fan P., Qian M., He X., Wu S., Zhang Y., Zheng X. Eur. J. Med. Chem. 2019, 186, 111893. https://doi.org/10.1016/j.ejmech.2019.111893
  15. Queiroz A.N., Martins C.C., Santos K.L.B., Car-valho E.S., Owiti A.O., Oliveira K.R.M., Herculano A.M., da Silva A.B.F., Borges R.S. Saudi Pharm. J. 2020, 28, 819–827. https://doi.org/10.1016/j.jsps.2020.06.001
  16. Miyaji Y., Yoshimura S., Sakai N., Yamagami H., Egashira Y., Shirakawa M., Uchida K., Kageyama H., Tomogane Y. Neurol. Med. Chir. 2015, 55, 241­247. https://doi.org/10.2176/nmc.ra.2014-0219.
  17. Sun Z., Xu Q., Gao G., Zhao M., Sun C. Niger. J. Clin. Pract. 2019, 22, 1324­–1327. https://doi.org/10.4103/njcp.njcp_367_18
  18. Luo L., Song Z., Li X., Huiwang, Zeng Y., Qinwang, Meiqi, He J. Neurol. Sci. 2019, 40, 235–241. https://doi.org/10.1007/s10072-018-3653-2
  19. Shefner J., Heiman‐Patterson T., Pioro E.P., Wiedau‐Pazos M., Liu S., Zhang J., Agnese W., Apple S. Muscle Nerve. 2020, 61, 218–221. https://doi.org/10.1002/mus.26740
  20. Burgart Y.V., Elkina N.A., Shchegolkov E.V., Krasnykh O.P., Makhaeva G.F., Triandafilova G.A., Solodnikov S.Y., Boltneva N.P., Rudakova E.V., Kovaleva N.V., Serebryakova O.G., Ulitko M.V., Borisevich S.S., Gerasimova N.A., Evstigneeva N.P., Kozlov S.A., Korolkova Y.V., Minin A.S., Belousova A.V., Mozhaitsev E.S., Klabukov A.M., Saloutin V.I. Molecules. 2023, 28, 59. https://doi.org/10.3390/molecules28010059
  21. Edilova Y.O., Kudyakova Y.S., Kiskin M.A., Burgart Y.V., Saloutin V.I., Bazhin D.N. J. Fluor. Chem. 2022, 253, 109932. https://doi.org/10.1016/j.jfluchem.2021.109932
  22. Bazhin D.N., Kudyakova Y.S., Onoprienko A.Ya., Slepukhin P.A., Burgart Y.V., Saloutin V.I. Chem. Heterocycl. Comp. (Eng. Trans.) 2017, 53, 1324–1329. https://doi.org/10.1007/s10593-018-2214-1
  23. Bazhin D.N., Kudyakova Y.S., Röschenthaler G.V., Burgart Y.V., Slepukhin P.A., Isenov M.L., Saloutin V.I., Charushin V.N. Eur. J. Org. Chem. 2015, 5236–5245. https://doi.org/10.1002/ejoc.201500737
  24. Surowiak A.K., Lochyński S., Strub D.J. Symmetry. 2020, 12, 575. https://doi.org/10.3390/sym12040575
  25. Özen T., Bal A., Topcu S., Taş M. Pharm. Pharmacol. Int. J. 2021, 9, 176‒192. https://doi.org/10.15406/ppij.2021.09.00343
  26. Kosmalski T., Kupczyk D., Baumgart S, Paprocka R., Studzińska R. Molecules. 2023, 28, 5041. https://doi.org/10.3390/molecules28135041
  27. Oh J.M., Rangarajan T.M., Chaudhary R., Singh R.P., Singh M., Singh R.P., Tondo A.R., Gambacorta N., Nicolotti O., Mathew B., Kim H. Molecules. 2020, 25, 2356. https://doi.org/10.3390/molecules25102356
  28. Makhaeva G.F., Rudakova E.V., Kovaleva N.V., Lushchekina S.V., Boltneva N.P., Proshin A.N., Shchegolkov E.V., Burgart Y.V., Saloutin V.I. Russ. Chem. Bull. 2019, 68, 967–984. https://doi.org/10.1007/s11172-019-2507-2
  29. LeVine H. 3rd. Methods Enzymol. 1999, 309, 274–284. https://doi.org/10.1016/s0076-6879(99)09020-5
  30. Munoz-Ruiz P., Rubio L., Garcia-Palomero E., Dorronsoro I., del Monte-Millan M., Valenzuela R., Usan P., de Austria C., Bartolini M., Andrisano V., Bidon-Chanal A., Orozco M., Luque F.J., Medina M., Martinez A. J. Med. Chem. 2005, 48, 7223–7233. https://doi.org/10.1021/jm0503289
  31. Re R., Pellegrini N., Proteggente A., Pannala A., Yang M., Rice-Evans C. Free Radical Biol. Med. 1999, 26, 1231–1237. https://doi.org/10.1016/s0891-5849(98)00315-3
  32. Benzie I.F.F., Strain J.J. Methods Enzymol. 1999, 299, 15–27. https://doi.org/10.1016/s0076-6879(99)99005-5
  33. Dolomanov O.V., Bourhis L.J., Gildea R.J., Howard J.A.K., Puschmann H. J. Appl. Cryst. 2009, 42, 339–341. https://doi.org/10.1107/S0021889808042726
  34. Sheldrick G.M. Acta Cryst. 2008, A64, 112–122. https://doi.org/10.1107/S0108767307043930
  35. Bazhin D.N., Chizhov D.L., Roschenthaler G.V., Kudyakova Y.S., Burgart Y.V., Slepukhin P.A., Saloutin V.I., Charushin V.N. Tetrahedron Lett. 2014, 55, 5714–5717. https://doi.org/10.1016/j.tetlet.2014.08.046
  36. Ellman G.L., Courtney K.D., Andres V., Feathersto-ne R.M. Biochem. Pharmacol. 1961, 7, 88­–95. https://doi.org/10.1016/0006-2952(61)90145-9
  37. Makhaeva G.F., Kovaleva N.V., Boltneva N.P., Lushchekina S.V., Rudakova E.V., Stupina T.S., Terentiev A.A., Serkov I.V., Proshin A.N., Radchen-ko E.V., Palyulin V.A., Bachurin S.O., Richardson R.J. Bioorg. Chem. 2020, 94, 103387. https://doi.org/10.1016/j.bioorg.2019.103387
  38. Makhaeva G.F., Elkina N.A., Shchegolkov E.V., Boltneva N.P., Lushchekina S.V., Serebryakova O.G., Rudakova E.V., Kovaleva N.V., Radchenko E.V., Palyulin V.A., Burgart Ya.V., Saloutin V.I., Bachurin S.O., Richardson R.J. Bioorg. Chem. 2019, 91, 103097. https://doi.org/10.1016/j.bioorg.2019.103097
  39. Makhaeva G.F., Kovaleva N.V., Boltneva N.P., Lushchekina S.V., Astakhova T.Y., Rudakova E.V., Proshin A.N., Serkov I.V., Radchenko E.V., Palyulin V.A., Bachurin S.O., Richardson R.J. Molecules. 2020, 25, 3915. https://doi.org/10.3390/molecules25173915
  40. Biancalana M., Koide S. Biochim. Biophys. Acta. 2010, 1804, 1405–1412. https://doi.org/10.1016/j.bbapap.2010.04.001
  41. Makhaeva G.F., Proshin A.N., Kovaleva N.V., Rudakova E.V., Boltneva N.P., Lushchekina S.V., Astakhova T.Y., Serkov I.V., Kalashnikova I.P., Bachurin S.O. Russ. Chem. Bull. 2022, 71, 2404–2415. https://doi.org/10.1007/s11172-022-3668-y

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Russian Academy of Sciences

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).