vuzbiochemiИзвестия вузов. Прикладная химия и биотехнологияProceedings of Universities. Applied Chemistry and Biotechnology2227-29252500-1558ИРНИТУ10.21285/2227-2925-2022-12-1-167-172vuzbiochemi-763Research ArticleКРАТКИЕ СООБЩЕНИЯBRIEF COMMUNICATIONСинтез и характеристика тиосемикарбазонов 2,5-дибутилтио-2,3-дигидро-2-формил-4Н-пирана и их медных комплексовSynthesis and characterization of 2,5-dibutylthio-2,3-dihydro-2-formyl-4H-pyran thiosemicarbazones and their copper complexeshttps://orcid.org/0000-0003-4907-5612ВерочкинаЕ. А.VerochkinaE. A.

Е. А. Верочкина, к.х.н., научный сотрудник664033, г. Иркутск, ул. Фаворского, 1

Ekaterina A. Verochkina, Cand. Sci. (Chemistry), Researcher

1, Favorsky St., Irkutsk, 664033

kleptsova84@mail.ruhttps://orcid.org/0000-0002-1921-0257ВчислоН. В.VchisloN. V.

Н. В. Вчисло, к.х.н., научный сотрудникм664033, г. Иркутск, ул. Фаворского, 1

Nadezhda V. Vchislo, Cand. Sci. (Chemistry), Researcher1, Favorsky St., Irkutsk, 664033

vchislo@bk.ruhttps://orcid.org/0000-0002-7388-712XЛаринаЛ. И.LarinaL. I.

Л. И. Ларина, д.х.н., ведущий научный сотрудник664033, г. Иркутск, ул. Фаворского, 1

Lyudmila I. Larina, Dr. Sci. (Chemistry), Leading Researcher

1, Favorsky St., Irkutsk, 664033

larina@irioch.irk.ruhttps://orcid.org/0000-0002-0665-8060ТитовЕ. А.TitovE. A.

Е. А. Титов, к.б.н., старший научный сотрудник665827, г. Ангарск, 12-А микрорайон, 3

Evgenii A. Titov, Cand. Sci. (Biology), Senior Researcher,East-Siberian Institute of Medical and Ecological Research

12a microdistrict, 3, Angarsk, 665827

g57097@yandex.ruИркутский институт химии им. А. Е. Фаворского СО РАНРоссияA. E. Favorsky Irkutsk Institute of Chemistry SB RASRussian FederationИркутский институт химии им. А. Е. Фаворского СО РАН; Восточно-Сибирский институт медико-экологических исследованийРоссияA. E. Favorsky Irkutsk Institute of Chemistry SB RAS; East-Siberian Institute of Medical and Ecological ResearchRussian Federation202201042022121167172Copyright © Верочкина Е.А., Вчисло Н.В., Ларина Л.И., Титов Е.А., 20222022Верочкина Е.А., Вчисло Н.В., Ларина Л.И., Титов Е.А.Verochkina E.A., Vchislo N.V., Larina L.I., Titov E.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vuzbiochemi.elpub.ru/jour/article/view/763

Неизвестные ранее производные тиосемикарбазида получены путем реакции конденсации 2,5-дибутилтио-2,3-дигидро-2-формил-4Н-пирана с 4-фенилтиосемикарбазидом или тиосемикарбазидом при кипячении в EtOH с высокими выходами. Продукты представляют собой окрашенные масла. Комплексы Cu(II) на основе карбазонов 2,5-дибутилтио-2,3-дигидро-2-формил-4Н-пирана были синтезированы путем взаимодействия с хлоридом меди (II). Все эти комплексы растворимы в диметилформамиде (ДМФА) и диметилсульфоксиде (ДМСО), элементный анализ показывает, что они имеют стехиометрию 1:1 металл–лиганд. Структуры полученных соединений охарактеризованы методами ИК и 1Н, 13С, 15N ЯМР-спектроскопии и элементного анализа. Полученные медьсодержащие комплексы с тиосемикарбазонами представляют интерес в связи с их повышенной биологической активностью. Сделан первичный скрининг острой токсичности соединения тиосемикарбазон 2,5-дибутилтио-2,3- дигидро-2-формил-4Н-пирана. Анализ полученных результатов показал, что по параметру DL50 исследуемый препарат при остром внутрижелудочном пути поступления характеризуется как вещество, имеющее низкую опасность острой токсичности, и относится к V классу опасности (DL50>2000 мг/кг).

Previously unknown derivatives of thiosemicarbazide were obtained in high yields by the condensation reaction of 2,5-dibutylthio-2,3-dihydro-2-formyl-4H-pyran with 4-phenylthiosemicarbazide or thiosemicarbazide when boiling in EtOH. The reaction products are represented by colored oils. Cu(II) complexes based on 2,5-dibutylthio-2,3-dihydro-2-formyl-4H-pyran carbazones were synthesized by their interaction with copper (II) chloride. All these complexes are soluble in dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) and, according to elemental analysis, have a 1:1 metal-ligand stoichiometry. The obtained compounds were studied using IR and 1H, 13C, 15N NMR spectroscopy, as well as elemental analysis. The obtained copper-containing complexes with thiosemicarbazones are of particular interest due to their pronounced biological activity. The thiosemicarbazone 2,5-dibutylthio-2,3-dihydro-2-formyl-4H-pyran compound was subjected to primary screening for acute toxicity. The obtained results showed that, when taken intragastricaly, the studied compound can be characterized as a substance with a low risk of acute toxicity. According to the DL50 parameter, the compound belongs to the V hazard class (DL50>2000 mg/kg).

25-дибутилтио-23-дигидро-2-формил-4Н-пиран4-фенилтиосемикарбазидтиосемикарбазидметаллокомплексыбиологическая активность25-dibutylthio-23-dihydro-2-formyl-4H-pyran4-phenylthiosemicarbazidethiosemicarbazidemetal complexesbiological activityReferencesMetwally M. A., Bondock S., Hossam E.-A., Kandeel E.-E. M. Thiosemicarbazides: synthesis and reactions // Journal of Sulfur Chemistry. 2011. Vol. 32, no. 5. P. 489–519. https://doi.org/10.1080/ 17415993.2011.601869.Metwally M. A., Bondock S., Hossam E.-A., Kandeel E.-E. M. Thiosemicarbazides: synthesis and reactions. Journal of Sulfur Chemistry. 2011;32(5):489-519. https://doi.org/10.1080/17415993.2011.601869.Desai S. B., Desai P. B., Desai K. R. Synthesis of some Schiff bases, thiazolidinones and azetidinones derived from 2,6-diaminobenzo[1,2-d:4,5-d’] bisthiazole and their anticancer activities // Heterocyclic Communications. 2001. Vol. 7, no. 1. P. 83–90. https:// doi.org/10.1515/HC.2001.7.1.83.Desai S. B., Desai P. B., Desai K. R. Synthesis of some Schiff bases, thiazolidinones and azetidinones derived from 2,6-diaminobenzo[1,2-d:4,5- d’] bisthiazole and their anticancer activities. Heterocyclic Communications. 2001;7(1):83-90. https:// doi.org/10.1515/HC.2001.7.1.83.Kumar R. S., Arunachalam S. DNA binding and antimicrobial studies of polymer–copper(II) complexes containing 1,10-phenanthroline and L-phenylalanine ligands // European Journal of Medicinal Chemistry. 2009. Vol. 44, no. 5. P. 1878–1883. https://doi.org/10. 1016/j.ejmech.2008.11.001.Kumar R. S., Arunachalam S. DNA binding and antimicrobial studies of polymer–copper(II) complexes containing 1,10-phenanthroline and L-phenylalanine ligands. European Journal of Medicinal Chemistry. 2009; 44(5):1878-1883. https://doi.org/10.1016/j.ejmech.2 008.11.001.Samadhiya S., Halve A. Synthetic utility of Schiff bases as potential herbicidal agents // Oriental Journal of Chemistry. 2001. Vol. 17, no. 1. P. 119–122.Samadhiya S., Halve A. Synthetic utility of Schiff bases as potential herbicidal agents. Oriental Journal of Chemistry. 2001;17(1):119-122.Vanco J., Marek J., Travnicek Z., Racanska E., Muselik J., Svajlenova O. Synthesis, structural characterization, antiradical and antidiabetic activities of copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and β-alanine // Journal of Inorganic Biochemistry. 2008. Vol. 102, no. 4. P. 595–605. https:// doi.org/10.1016/j.jinorgbio.2007.10.003.Vanco J., Marek J., Travnicek Z., Racanska E., Muselik J., Svajlenova O. Synthesis, structural characterization, antiradical and antidiabetic activities of copper(II) and zinc(II) Schiff base complexes derived from salicylaldehyde and β-alanine. Journal of Inorganic Biochemistry. 2008;102(4):595-605. https://doi. org/10.1016/j.jinorgbio.2007.10.003.Tarushi A., Polatoglou E., Kljun J., Turel I., Psomas G., Kessissoglou D. P. Interaction of Zn(II) with quinolone drugs: structure and biological evaluation // Dalton Transactions. 2011. Vol. 40. P. 9461– 9473. https://doi.org/10.1039/c1dt10870k.Tarushi A., Polatoglou E., Kljun J., Turel I., Psomas G., Kessissoglou D. P. Interaction of Zn(II) with quinolone drugs: structure and biological evaluation. Dalton Transactions. 2011;40:9461-9473. https:// doi.org/10.1039/c1dt10870k.Andres S. A., Bajaj K., Vishnosky N. S., Peterson M. A., Mashuta M. S., Buchanan R. M., et al. Synthesis, characterization, and biological activity of hybrid thiosemicarbazone–alkylthiocarbamate metal complexes // Inorganic Chemistry. 2020. Vol. 59, no. 7. P. 4924–4935. https://doi.org/10.1021/acs.inorgchem. 0c00182.Andres S. A., Bajaj K., Vishnosky N. S., Peterson M. A., Mashuta M. S., Buchanan R. M., et al. Synthesis, characterization, and biological activity of hybrid thiosemicarbazone–alkylthiocarbamate metal complexes. Inorganic Chemistry. 2020;59(7):4924- 4935. https://doi.org/10.1021/acs.inorgchem.0c00182.Laverick R. J., Zhang N., Reid E., Kim J., Kilpin K. J., Kitchen J. A. Solution processible Co(III) quinoline-thiosemicarbazone complexes: synthesis, structure extension, and Langmuir-Blodgett deposition studies // Journal of Coordination Chemistry. 2021. Vol. 74, no. 1-3. P. 321–340. https://doi.org/ 10.1080/00958972.2021.1879384.Laverick R. J., Zhang N., Reid E., Kim J., Kilpin K. J., Kitchen J. A. Solution processible Co(III) quinoline-thiosemicarbazone complexes: synthesis, structure extension, and Langmuir-Blodgett deposition studies. Journal of Coordination Chemistry. 2021;74(1-3):321- 340. https://doi.org/10.1080/00958972.2021.1879384.Пат. № 1727243, СССР. Применение 2-формил-2,5-дибутилтио-2,3-дигидро-4Н-пирана в качестве дезинфицирующего средства / Н. П. Баркова, Н. А. Кейко, Л. Г. Степанова, М. Г. Воронков, А. А. Портяной, Т. И. Никифорова; патентообладатель Иркутский институт органической химии СО РАН. Заявл. 16.02.1990; опубл. 20.10.1999. Бюл. № 33.Barkova N. P., Keiko N. A., Stepanova L. G., Voronkov M. G., Portyanoi A. A., Nikiforova T. I. Application of 2-formyl-2,5-dibutylthio-2,3-dihydro-4H-pyran as a disinfectant. Patent USSR, no. 1727243; 1999. (In Russian).А.С. № 297635, СССР. Способ получения 2-формил-2,5-дибутилтио-2,3-дигидро-γ-пиранов / М. Ф. Шостаковский, Н. А. Кейко, Л. Г. Степанова, Е. Б. Пышная. Заявл. 16.10.1969; опубл. 11.03.1971. Бюл. № 10.Shostakovskii M. F., Keiko N. A., Stepanova L. G., Pyshnaya E. B. Method for the preparation of 2-formyl2,5-dibutylthio-2,3-dihydro-γ-pyrans. Certificate of authorship USSR, no. 297635; 1971. (In Russian).Кейко Н. А., Степанова Л. Г., Калихман И. Д., Воронков М. Г. Новые 2-формил-2,5-дибутилтио2,3-дигидро-γ-пираны // Известия Академии наук СССР. Серия химическая. 1977. Т. 7. С. 1652–1655.Keiko N. A., Stepanova L. G., Kalikhman I. D., Voronkov M. G. New 2-formyl-2,5-dibutylthio-2,3-dihydroγ-pyrans. Izvestiya Akademii nauk SSSR. Seriya khimicheskaya. 1977;7:1652-1655. (In Russian).Prajapati N. P., Patel H. D. Novel thiosemicarbazone derivatives and their metal complexes: recent development // Synthetic Communications. 2019. Vol. 49, no. 21. P. 2767–2804. https://doi.org/ 10.1080/00397911.2019.1649432.Prajapati N. P., Patel H. D. Novel thiosemicarbazone derivatives and their metal complexes: recent development. Synthetic Communications. 2019; 49(21):2767-2804. https://doi.org/10.1080/00397911.2 019.1649432.Kostas I. D., Steele B. R. Thiosemicarbazone complexes of transition metals as catalysts for crosscoupling reactions // Catalysts. 2020. Vol. 10. P. 1107– 1147. https://doi.org/10.3390/catal10101107.Kostas I. D., Steele B. R. Thiosemicarbazone complexes of transition metals as catalysts for cross-coupling reactions. Catalysts. 2020;10:1107- 1147. https://doi.org/10.3390/catal10101107.Lin L. F., Lee S. J., Chen C.-T. Studies on potential antitumor agents (II). Thiosemicarbazones of pbromophenyl- and o-chlorophenylpyridine-2-carboxaldehydes // Heterocycles. 1977. Vol. 7, no. 1. P. 347– 352. https://doi.org/10.3987/S-1977-01-0347.Lin L. F., Lee S. J., Chen C.-T. Studies on potential antitumor agents (II). Thiosemicarbazones of p-bromophenyl- and o-chlorophenylpyridine-2- carboxaldehydes. Heterocycles. 1977;7(1):347-352. https://doi.org/10.3987/S-1977-01-0347.Gatto C. C., Lima F. C., Miguel P. M. Copper(II) complexes with semicarbazones: synthesis, characterization and noncovalent interactions in their crystal structures // Journal of Chemical Sciences. 2020. P. 132–146. Article number 146. https://doi. org/10.1007/s12039-020-01847-5.Gatto C. C., Lima F. C., Miguel P. M. Copper(II) complexes with semicarbazones: synthesis, characterization and noncovalent interactions in their crystal structures. Journal of Chemical Sciences. 2020;132-146. Article number 146. https://doi. org/10.1007/s12039-020-01847-5.Todorović T. R., Vukašinović J., Portalone G., Suleiman S., Gligorijević N., Bjelogrlić S., et al. (Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines // Medicinal Chemistry Communications. 2017. Vol. 8, no. 1. P. 103–111. https://doi.org/10.1039/c6md00501b.Todorović T. R., Vukašinović J., Portalone G., Suleiman S., Gligorijević N., Bjelogrlić S., et al. (Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines. Medicinal Chemistry Communications. 2017;8(1):103-111. https://doi.org/1 0.1039/c6md00501b.Khan T., Ahmad R., Joshi S., Khan A. R. Anticancer potential of metal thiosemicarbazone complexes: a review // Der Chemica Sinica. 2015. Vol. 6, no. 12. P. 1–11.Khan T., Ahmad R., Joshi S., Khan A. R. Anticancer potential of metal thiosemicarbazone complexes: a review. Der Chemica Sinica. 2015;6(12):1-11.Palamarciuc O., Milunović M. N. M., Sîrbu A., Stratulat E., Pui A., Gligorijevic N., et al. Investigation of the cytotoxic potential of methyl imidazolederived thiosemicarbazones and their copper(II) complexes with dichloroacetate as a co-ligand // New Journal of Chemistry. 2019. Vol. 43, no. 3. P. 1340–1357. https://doi.org/10.1039/C8NJ04041A.Palamarciuc O., Milunović M. N. M., Sîrbu A., Stratulat E., Pui A., Gligorijevic N., et al. Investigation of the cytotoxic potential of methyl imidazolederived thiosemicarbazones and their copper(II) complexes with dichloroacetate as a co-ligand. New Journal of Chemistry. 2019;43(3):1340-1357. https:// doi.org/10.1039/C8NJ04041A.

The authors declare that there are no conflicts of interest present.