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Synthesis and Biological Activity of Substituted 2-[2-(Diphenylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates

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Abstract

The synthesis of new substituted 2-[2-(diphenylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates is described. The synthesis from commercially available starting materials included the preparation of 5,5-dimethyl-2,4-dioxohexanoic acid via Claisen condensation of 3,3-dimethylbutan-2-one (pinacolone) and diethyl oxalate in the presence of sodium methanolate. The resulting acid reacted with (diphenylmethylene)hydrazine to form 2-[(diphenylmethylene)hydrazono]-5,5-dimethyl-4-oxohexanoic acid. The initial 5-(tert-butyl)-3-[(diphenylmethylene)hydrazono]furan-2(3H)-one was obtained by a known literary method: intramolecular cyclisation of 2-[(diphenylmethylene)hydrazono]-5,5-dimethyl-4-oxohexanoic acid under the action of propionic anhydride. 5-(tert-Butyl)-3-[(diphenylmethylene)hydrazono]furan-2(3H)-one entered the decyclization reaction under the action of primary aromatic alcohols to form substituted 2-[2-(diphenylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates. The presence of equimolar quantities of triethylamine was important; otherwise, the reaction proceeded with low yields. The isolation of target compounds was carried out by filtration of the resulting sediment followed by recrystallization. The structure of the compounds obtained was confirmed by the 1H and 13C NMR spectroscopy methods. The resulting substituted esters exist in a solution of deuterated chloroform in one tautomeric form, in contrast to the previously studied solutions of deuterated DMSO, where up to four tautomeric forms were observed. Analgesic and anti-inflammatory activity of new and previously synthesized compounds of this series has been studied. Analgesic activity was evaluated by the “Hot Plate” test on outbred white mice of both sexes with intraperitoneal injection. Anti-inflammatory activity was studied on a carrageenan-induced paw edema model with oral administration of the studied substances. One compound possesses both high analgesic and high anti-inflammatory effects, which causes the prospects for its use as a pharmacologically active substance.

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REFERENCES

  1. Kozhukhar, V.Y., Candidate Sci. (Chem.) Dissertation, Perm, 2016.

  2. Kuznetsov, A.S., Candidate Sci. (Chem.) Dissertation, Perm, 2016.

  3. Rubtsov, A.E., Kovylyaeva, N.V., and Zalesov, V.V., Pharm. Chem. J., 2005, vol. 39, p. 11. https://doi.org/10.1007/s11094-005-0069-0

    Article  CAS  Google Scholar 

  4. Elkholy, Y.M., Ali, K.A., and Farag, A.M., Phosphorus Sulfur and Silicon Relat. Elem., 2006, vol. 181, p. 2037. https://doi.org/10.1080/10426500600605731

    Article  CAS  Google Scholar 

  5. Zalesov, V.V., Rubtsov, A.E., and Bystritskaya, О.А., Russ. J. Org. Chem., 2007, vol. 43, p. 1415. https://doi.org/10.1134/S107042800709028X

    Article  CAS  Google Scholar 

  6. Rubtsov, A.E., Aliev, Z.G., and Maiorova, O.A., Russ. J. Org. Chem., 2010, vol. 46, p. 933. https://doi.org/10.1134/s107042801006028x

    Article  CAS  Google Scholar 

  7. Maiorova, O.A., Babkina, N.V., and Egorova, A.Y., Chem. Heterocycl. Compd., 2015, vol. 51, p. 514. https://doi.org/10.1007/s10593-015-1730-5

    Article  CAS  Google Scholar 

  8. Elkholy, Y.M., Ali, K.A., and Farag, A.M., J. Heterocycl. Chem., 2006, vol. 5, p. 1183. https://doi.org/10.1002/jhet.5570430508

    Article  Google Scholar 

  9. Sayed, H.H., Hashem, A.I., Yousif, N.M., and El-Sayed, W.A., Arch. Pharm., 2007, vol. 340, p. 315. https://doi.org/10.1002/ardp.200700043

    Article  CAS  Google Scholar 

  10. Gavkus, D.N., Maiorova, O.A., Borisov, M.Y., and Egorova, A.Y., Russ. J. Org. Chem., 2012, vol. 48, p. 1229. https://doi.org/10.1134/S107042801209014X

    Article  CAS  Google Scholar 

  11. Maigali, S.S., El-Hussieny, M., and Soliman, F.M., J. Heterocycl. Chem., 2015, vol. 52, p. 15. https://doi.org/10.1002/jhet.1911

    Article  CAS  Google Scholar 

  12. Mayorova, O.A., and Yegorova, A.Y., Magn. Reson. Chem., 2015, vol. 53, p. 853. https://doi.org/10.1002/mrc.4270

    Article  CAS  PubMed  Google Scholar 

  13. Maiorova, O.A., Grinev, V.S., and Yegorova, A.Y., J. Struct. Chem., 2015, vol. 56, p. 803. https://doi.org/10.1134/S0022476615040320

    Article  CAS  Google Scholar 

  14. Mokhonova, I.D., Maksimov, E.A., Ledenyona, I.V., Yegorova, A.Y., and Shikhaliev, K.S., Heterocycl. Commun., 2018, vol. 24, p. 183. https://doi.org/10.1515/hc-2017-0192

    Article  CAS  Google Scholar 

  15. Siutkina, A.I., Igidov, N.M., Dmitriev, M.V., Makhmudov, R.R., and Novikova, V.V., Russ. J. Gen. Chem., 2019, vol. 89, p. 1388. https://doi.org/10.1134/S1070363219070065

    Article  CAS  Google Scholar 

  16. Rubtsov, A.E. and Zalesov, V.V., Russ. J. Org. Chem., 2003, vol. 39, p. 869. https://doi.org/10.1023/B:RUJO.0000003167.28537.71

    Article  CAS  Google Scholar 

  17. Zalesov, V.V. and Rubtsov, A.E., Chem. Heterocycl. Compd., 2004, vol. 2, p. 133. https://doi.org/10.1023/b:cohc.0000027884.75379.14

    Article  Google Scholar 

  18. Pulina, N.A., Kuznetsov, A.S., and Rubtsov, A.E., Russ. J. Org. Chem., 2015, vol. 51, p. 967. https://doi.org/10.1134/s1070428015070131

    Article  CAS  Google Scholar 

  19. Kozminykh, V.O., Belyaev, A.O., and Kozminykh, E.N., Chem. Heterocycl. Compd., 2003, vol. 39, p. 1107. https://doi.org/10.1023/B:COHC.0000003533.52494.dd

    Article  CAS  Google Scholar 

  20. Kizimova, I.A., Igidov, N.M., Kiselev, M.A., Syutkina, A.I., and Ivanov, D.V., Russ. J. Gen. Chem., 2020, vol. 90, p. 815. https://doi.org/10.1134/S1070363220050096

    Article  CAS  Google Scholar 

  21. Rubtsov, A.E. and Zalesov, V.V., Russ. J. Org. Chem., 2007, vol. 43, p. 735. https://doi.org/10.1134/S1070428007050156

    Article  CAS  Google Scholar 

  22. Zykova, S.S., Kizimova, I.A., Syutkina, A.I., Toksarova, Yu.S., Igidov, N.M., Ibishov, D.F., Boichuk, S.V., Dunaev, P.D., and Galembikova, A.R., Pharm. Chem. J., 2020, vol. 53, p. 895. https://doi.org/10.1007/s11094-020-02096-z

    Article  CAS  Google Scholar 

  23. Kizimova, I.A., Igidov, N.M., Kiselev, M.A., Dmitriev, M.V., Chashchina, S.V., and Siutkina, A.I., Russ. J. Gen. Chem., 2020, vol. 90, p. 182. https://doi.org/10.1134/S1070363220020036

    Article  CAS  Google Scholar 

  24. Pulina, N.A., Kozhukhar, V.Y., Kuznetsov, A.S., Rubtsov, A.E., and Starkova, A.V., Russ. Chem. Bull., 2017, vol. 8, p. 1497. https://doi.org/10.1007/s11172-017-1914-5

    Article  CAS  Google Scholar 

  25. Cvijetic, I., Verbic, T., Drakulic, B., Stankovic, D., Juranic, I., Manojlovic, D., and Zloh, M., J. Serb. Chem. Soc., 2017, vol. 3, p. 303–316. https://doi.org/10.2298/jsc161118021c

    Article  CAS  Google Scholar 

  26. Saleh, T.A.-K., Al-Samarai, R.R.H., and Abdul-Razzaq, N.E., IJRPS, 2019, vol. 10, p. 1510. https://doi.org/10.26452/ijrps.v10i2.730

    Article  CAS  Google Scholar 

  27. Braga, R., Hecquet, L., and Blonski, C., Bioorg. Med. Chem., 2004, vol. 12, p. 2965. https://doi.org/10.1016/j.bmc.2004.03.039

    Article  CAS  PubMed  Google Scholar 

  28. Drakulic, B.J., Stavri, M., Gibbons, S., Zizak, Z.S., Verbic, T.Z., Juranic, I.O., and Zloh, M., ChemMedChem., 2009, vol. 4, p. 1971. https://doi.org/10.1002/cmdc.200900273

    Article  CAS  PubMed  Google Scholar 

  29. Baughman, B.M., Slavish, P.J., DuBois, R.M., Boyd, V.A., White, S.W., and Webb, T.R., ACS Chem. Biol., 2012, vol. 7, p. 526. https://doi.org/10.1021/cb200439z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. de Melo, E.B. and Ferreira, M.M., J. Chem. Inf. Model., 2012, vol. 52, p. 1722. https://doi.org/10.1021/ci300039a

    Article  CAS  PubMed  Google Scholar 

  31. Kowalinski, E., Zubieta, C., Wolkerstorfer, A., Szolar, O.H., Ruigrok, R.W., and Cusack, S., PloS Pathogens, 2012, vol. 8, e1002831. https://doi.org/10.1371/journal.ppat.1002831

  32. Sharma, H., Sanchez, T.W., Neamati, N., Detorio, M., Schinazi, R.F., Cheng, X., and Buolamwini, J.K., Bioorg. Med. Chem. Lett., 2013, vol. 23, p. 6146. https://doi.org/10.1016/j.bmcl.2013.09.009

    Article  CAS  PubMed  Google Scholar 

  33. Wai, J.S., Egbertson, M.S., Payne, L.S., Fisher, T.E., Embrey, M.W., Tran, L.O., Melamed, J.Y., Langford, H.M., Guare, J.P. Jr., Zhuang, L., Grey, V.E., Vacca, J.P., Holloway, M.K., Naylor-Olsen, A.M., Hazuda, D.J., Felock, P.J., Wolfe, A.L., Stillmock, K.A., Schleif, W.A., Gabryelski, L.J., and Young, S.D., J. Med. Chem., 2000, vol. 26, p. 4923. https://doi.org/10.1021/jm000176b

    Article  CAS  Google Scholar 

  34. Shaw-Reid, C.A., Munshi, V., Graham, P., Wolfe, A., Witmer, M., Danzeisen, R., Olsen, D.B., Carroll, S.S., Embrey, M., Wai, J.S., Miller, M.D., Cole, J.L., and Hazuda, D.J., J. Biol. Chem., 2003, vol. 5, p. 2777. https://doi.org/10.1074/jbc.C200621200

    Article  CAS  Google Scholar 

  35. Uchil, V., Seo, B., and Nair, V., J. Org. Chem., 2007, vol. 72, p. 8577. https://doi.org/10.1021/jo701336r

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dias, A., Bouvier, D., Crepin, T., McCarthy, A.A., Hart, D.J., Baudin, F., Cusack, S., and Ruigrok, R.W., Nature, 2009, vol. 458, p. 914. https://doi.org/10.1038/nature07745

    Article  CAS  PubMed  Google Scholar 

  37. Michelini, Z., Galluzzo, C.M., Negri, D.R., Leone, P., Amici, R., Bona, R., Summa, V., Di Santo, R., Costi, R., Pommier, Y., Marchand, C., Palmisano, L., Vella, S., and Cara, A., J. Virol. Methods., 2010, vol. 168, p. 272. https://doi.org/10.1016/j.jviromet.2010.06.004

    Article  CAS  PubMed  Google Scholar 

  38. Deore, R.R., Chen, G.S., Chen, C.S., Chang, P.T., Chuang, M.H., Chern, T.R., Wang, H.C., and Chern, J.W., Curr. Med. Chem., 2012, vol. 19, p. 613. https://doi.org/10.2174/092986712798918833

    Article  CAS  PubMed  Google Scholar 

  39. Hu, L., Zhang, S., He, X., Luo, Z., Wang, X., Liu, W., and Qin, X., Bioorg. Med. Chem., 2012, vol. 20, p. 177. https://doi.org/10.1016/j.bmc.2011.11.014

    Article  CAS  PubMed  Google Scholar 

  40. Costi, R., Di, Santo, R., Artico, M., Roux, A., Ragno, R., Massa, S., Tramontano, E., La Colla, M., Loddo, R., Marongiu, M.E., Pani, A., and La Colla, P., Bioorg. Med. Chem. Lett., 2004, vol. 7, p. 1745. https://doi.org/10.1016/j.bmcl.2004.01.037Hu

    Article  Google Scholar 

  41. Tramontano, E., Esposito, F., Badas, R., Di Santo, R., Costi, R., and La Colla, P., Antiviral, Res., 2005, vol. 2, p. 117. https://doi.org/10.1016/j.antiviral.2004.11.002

    Article  CAS  Google Scholar 

  42. Zhao, X.Z., Semenova, E.A., Liao, C., Nicklaus, M., Pommier, Y., and Burke, T.R. Jr., Bioorg. Med. Chem., 2006, vol. 23, p. 7816. https://doi.org/10.1016/j.bmc.2006.07.064

    Article  CAS  Google Scholar 

  43. Novikova, V.V., Pulina, N.A., Sobin, F.V., and Lipatnikov, K.V., Rev. Clin. Pharmacol. Drug Ther., 2020, vol. 18, p. 225. https://doi.org/10.17816/RCF183225-228

    Article  Google Scholar 

  44. Pulina, N.A., Zalesov, V.V., Bystritskaya, O.A., Rubtsov, A.E., and Kutkovaya, N.V., Pharm. Chem. J., 2009, vol. 43, p. 444. https://doi.org/10.1007/s11094-009-0334-8

    Article  CAS  Google Scholar 

  45. Kizimova, I.A., Igidov, N.M., Dmitriev, M.V., Chashchina, S.V., Makhmudov, R.R., and Siutkina, A.I., Russ. J. Gen. Chem., 2019, vol. 89, p. 2345. https://doi.org/10.1134/S107036321912003X

    Article  CAS  Google Scholar 

  46. Tumey, L.N., Huck, B., Gleason, E., Wang, J., Silver, D., Brunden, K., Boozer, S., Rundlett, S., Sherf, B., Murphy, S., Bailey, A., Dent, T., Leventhal, C., Harrington, J., and Bennani, Y.L., Bioorg. Med. Chem. Lett., 2004, vol. 14, p. 4915. https://doi.org/10.1016/j.bmcl.2004.07.028

    Article  CAS  PubMed  Google Scholar 

  47. Liu, S., Zeng, L.F., Wu, L., Yu, X., Xue, T., Gunawan, A.M., Long, Y.Q., and Zhang, Z.Y., J. Am. Chem. Soc., 2008, vol. 130, p. 17075. https://doi.org/10.1021/ja8068177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Siutkina, A.I., Igidov, N.M., and Kizimova, I.A., Russ. J. Org. Chem., 2020, vol. 56, p. 649. https://doi.org/10.1134/S1070428020040132

    Article  CAS  Google Scholar 

  49. Koz’minykh, V.O., Igidov, N.M., Berezina, E.S., Koz’minykh, E.N., and Kasatkina, Yu.S., Russ. Chem. Bull., 2000, vol. 49, p. 1552. https://doi.org/10.1007/BF02495160

    Article  Google Scholar 

  50. Komarova, O.A., Igidov, N.M., Koryagina, N.N. Makarov, A.S., Toksarova, Yu.S., and Rubtsov, A.E., Russ. J. Org. Chem., 2011, vol. 47, p. 109. https://doi.org/10.1134/S1070428011010131

    Article  CAS  Google Scholar 

  51. Mironov, A.N., Rukovodstvo po provedeniyu doklinicheskikh issledovanii lekarstvennykh sredstv (Guidelines for Conducting Preclinical Studies of Drugs), Part one, Moscow: Grif and K, 2012.

  52. Belenʼky, M.L., Elementy kolichestvennoi otsenki farmakologicheskogo effekta (Elements of Quantitative Evaluation of the Pharmacological Effect), 2nd Edn., Leningrad: Medgiz, 1963.

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Funding

The research was supported by the Perm Research and Education Centre for Rational Use of Subsoil, 2021.

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Authors and Affiliations

  1. Perm State Pharmaceutical Academy, Ministry of Health of the Russian Federation, 614990, Perm, Russia

    A. I. Siutkina, S. V. Chashchina, I. A. Kizimova & N. M. Igidov

  2. Perm State National Research University, 614068, Perm, Russia

    A. I. Siutkina, S. V. Chashchina, R. R. Makhmudov & S. A. Shipilovskikh

  3. Federal Scientific Center for Medical and Preventive Health Risk Management Technologies, 614045, Perm, Russia

    R. R. Makhmudov

  4. School of Physics and Engineering of the ITMO University, 197101, St. Petersburg, Russia

    S. A. Shipilovskikh

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  1. A. I. Siutkina
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  2. S. V. Chashchina
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Siutkina, A.I., Chashchina, S.V., Makhmudov, R.R. et al. Synthesis and Biological Activity of Substituted 2-[2-(Diphenylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates. Russ J Org Chem 57, 1874–1881 (2021). https://doi.org/10.1134/S1070428021110105

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