SYNTHESIS AND STUDY OF ANTINOCICEPTIVE ACTIVITY OF SUBSTITUTED 2-(3-CYANO-4,5,6,7-TETRAHYDROBENZO[B]THIOPHEN-2-YLAMINO)-4-OXOBUT-2-ENOATES
Abstract
In the current work, we present results the study of synthetic transformations of substituted 3-thienylimino-3H-furan-2-one derivatives containing a nitrile substituent in the third position of the thiophene ring under the action of nucleophilic reagents. This class of compounds is of great for study due to the presence of several reaction centers in its structure, which makes it possible to obtain products of various structures, while retaining important pharmacophore groups - fragments of 2-aminothiophene and a fragment of 2,4-dioxobutanoic acid. We have synthesized and studied for biological activity substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates, which were obtained by a multistep synthesis method. The proposed method provides high yields of target compounds and includes the reaction of 4-aryl-2-hydroxy-4-oxobutanoic acids with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile, followed by intramolecular cyclization of the resulting products under the action of propionic anhydride, as well as decyclization of the resulting substituted 3-thienylimino-3H-furan-2-ones under the action of primary alcohols. The structure of the finally isolated compounds was confirmed by 1H and 13C NMR spectroscopy and the elemental analysis. The resulting compounds were screened in vivo to detect and evaluate their biological activity and acute toxicity. Antinociceptive activity was studied in white outbred mice of both sexes by the hot plate test with intraperitoneal injection. Acute toxicity was studied according to the Pershin method, based on monitoring the condition of mice for 10 days after intraperitoneal injection of the test compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the assessment of acute toxicity indicates that they belong to the V class of practically non-toxic drugs. The high values of antinociceptive activity in combination with low toxicity make the considered substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates a highly promising class for further study in order to search for and develop new biologically active compounds with analgesic effect.
For citation:
Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Gorbunova I.A. Synthesis and study of antinociceptive activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 7. P. 19-27. DOI: 10.6060/ivkkt.20246707.7029.
References
Huang L., Yang J., Wang T., Gao J., Xu D. Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery. J. Nanobiotechnol. 2022. V. 20. N 49. P. 1-15. DOI: 10.1186/s12951-022-01257-4.
Zhao R., Fu J., Zhu L., Chen Y., Liu B. Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy. J. Hematol. Oncol. 2022. V. 15. N 14. P. 1-19. DOI: 10.1186/s13045-022-01230-6.
Babushkina A.A., Dogadina A.V., Egorov D.M., Piterskaia J.L., Shtro A.A., Nikolaeva Y.V., Galochkina A.V., Kornev A.A., Boitsov V.M. Efficient synthesis and evaluation of antiviral and antitumor activity of novel 3-phosphonylated thiazolo[3,2-a]oxopyrimidines. Med. Chem. Res. 2021. V. 30. N 12. P. 2203-2215. DOI: 10.1007/s00044-021-02801-x.
Yunnikova L.P., Akent’eva T.A., Suvorova Y.V., Danilova E.A., Islyaikin M.K. Tropylated 2-aminopyrimidines. Structural particuliarities and biological activity. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2022. V. 65. N 7. P. 35-44. DOI: 10.6060/ ivkkt.20226507.6562.
Siutkina A.I., Chashchina S.V., Makhmudov R.R., Kizimova I.A., Shipilovskikh S.A., Igidov N.M. Synthesis and Biological Activity of Substituted 2-[2-(Diphenylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enoates. Russ. J. Org. Chem. 2021. V. 57. P. 1874-1881. DOI: 10.1134/S1070428021110105.
Gorbunova I.A., Nikonov I.V., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Shipilovskikh S.A. Syn-thesis, intramolecular cyclization, and antinociceptive activity of 4-(het)aryl-2-{[4-(4-chlorophenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}-4-oxobut-2-enoic ac-ids. Izv. AN Ser. Khim. 2023. V. 72. N 9. P. 2255-2262 (in Russian). DOI: 10.1007/s11172-023-4023-7.
Siutkina A.I., Chashchina S.V., Makhmudov R.R., Novikova V.V., Chernov I.N., Igidov N.M. Synthesis, an-algesic and antimicrobial activity of N-hetarylamides of 2-(2-(diarylmethylene)hydrazono)-5,5-dimethyl-4-oxohexanoic acid. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2022. V. 65. N 3. P. 74-82. DOI: 10.6060/ivkkt.20226503.6522.
Fogue P.S., Lunga P.K., Fondjo E.S., De Dieu Tamokou J., Thaddée B., Tsemeugne J., Tchapi A.T., Kuiate J.R. Substituted 2‐aminothiophenes: antifungal activities and ef-fect on Microsporum gypseum protein profile. Mycoses. 2012. V. 55. N 4. P. 310-317. DOI: 10.1111/j.1439-0507. 2011.02089.x.
Panchamukhi S., Mohammed Iqbal A., Khan A., Kalashetti M., Khazi I. Synthesis, characterization, antibacterial and antifungal activity of thienopyrimidines and triazolothienopyrimidines. Pharm. Chem. J. 2011. V. 44. P. 694-696. DOI: 10.1007/s11094-011-0545-7.
Cvijetić I.N., Verbić T.Ž., Ernesto de Resende P., Stapleton P., Gibbons S., Juranić I.O., Drakulić B.J., Zloh M. Design, synthesis and biological evaluation of novel aryldiketo acids with enhanced antibacterial activity against multidrug resistant bacterial strains. Eur. J. Med. Chem. 2018. V. 143. P. 1474-1488. DOI: 10.1016/j.ejmech.2017.10.045.
Khalifa M.E., Algothami W.M. Gewald synthesis, antitumor profile and molecular modeling of novel 5-acetyl-4-((4-acetylphenyl)amino)-2-aminothiophene-3-carbonitrile scaffolds. J. Mol. Struct. 2020. V. 1207. P. 127784. DOI: 10.1016/j.molstruc.2020.127784.
Bobrovskaya O.V., Russkih A.A., Yankin A.N., Dmitriev M.V., Bunev A.S., Gein V.L. Straightforward synthesis of novel spiroether derivatives. Synth. Commun. 2021. V. 51. N 11. P. 1731-1741. DOI: 10.1080/00397911.2021.1903930.
Joksimović N., Janković N., Davidović G., Bugarčić Z. 2,4-Diketo esters: Crucial intermediates for drug discovery. Bioorg. Chem. 2020. V. 105. P. 104343. DOI: 10.1016/ j.bioorg.2020.104343.
Sharavyeva Yu.O., Gorbunova I.A., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Shipilovskikh S.A. Synthesis and antiinflammatory activity of 4-aryl-2-[(3-cyanothiophen-2-yl)amino]-4-oxobut-2-enoates. Izv. AN Ser. Khim. 2023. V. 72. N 12. P. 3005-3012 (in Russian). DOI: 10.1007/s11172-023-4112-7.
Babushkina A.A., Piterskaya Yu.L., Shtro A.A., Nikolaeva Yu.V., Galochkina A.V., Klabukov A.M., Egorov D.M. Synthesis, Phosphonylation, and Anti-Viral Activity of Some 6-Aryl-5-cyano-2-thiouracils. Russ. J. Gen. Chem. 2022. V. 92. N 1. P. 18-23. DOI: 10.1134/S1070363222010042.
Lipin D.V., Denisova E.I., Shipilovskikh D.A., Makhmudov R.R., Igidov N.M., Shipilovskikh S.A. Ring Opening of Substituted 3-[2-(4-Nitrobenzoyl) hydrazinyli-dene]furan-2(3H)-ones with Primary Alcohols. Analgesic Activity and Acute Toxicity of the Products. Russ. J. Org. Chem. 2023. V. 59. N 4. P. 631-638. DOI: 10.1134/S1070428023040103.
Lipin D.V., Metlyakova S.K., Shipilovskikh D.A., Makhmudov R.R., Silaichev P.S., Igidov N.M., Shipilovskikh S.A. Synthesis, antiinfl ammatory activity, and acute toxicity of the substituted 2-[2-(4-nitrobenzoyl)hydrazono]-4-oxobutanoates. Izv. AN Ser. Khim. 2023. V. 72. N 8. P. 1887-1893 (in Russian). DOI: 10.1007/s11172-023-3973-0.
Igidov S.N., Turyshev A.Yu., Makhmudov R.R., Shipilovskikh D.A., Igidov N.M., Shipilovskikh S.A. Synthesis, Intramolecular Cyclization, and Analgesic Activity of Substituted 2-[2-(Furancarbonyl)hydrazinylydene]-4-oxobutanoic Acids. Russ. J. Gen. Chem. 2022. V. 92. N 9. P. 1629-1636. DOI: 10.1134/S1070363222090067.
Lipin D.V., Denisova E.I., Devyatkin I.О., Okoneshnikova Е.А., Shipilovskikh D.A., Makhmudov R.R., Igi-dov N.M., Shipilovskikh S.A. Synthesis and Antinociceptive Activity of Substituted 5-(Het)aryl-3-(4-methylbenzoyl)hydrazono-3H-furan-2-ones. Russ. J. Gen. Chem. 2021. V. 91. N 12. P. 2469-2474. DOI: 10.1134/S1070363221120161.
Gorbunova I.A., Shipilovskikh D.A., Rubtsov A.E., Shipilovskikh S.A. Synthesis and Intramolecular Cycliza-tion of Substituted 4-(Het)aryl-4-oxo-2-thienylaminobut-2-enoic Acids Containing Nitrile Group in the Thiophene Ring. Russ. J. Gen. Chem. 2021. V. 91. N 9. P. 1623-1628. DOI: 10.1134/S1070363221090048.
Lipin D.V., Parkhoma K.Yu., Shadrin V.M., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Shipilovskikh S.A. Synthesis and antinociceptive activity of nitriles, esters, and amides of 2-amino-1-(3-cyano-4, 5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylic acids. Izv. AN Ser. Khim. 2023. V. 72. N 8. P. 1913-1920 (in Rus-sian). DOI: 10.1007/s11172-023-3976-x.
Igidov S.N., Turyshev A.Yu., Makhmudov R.R., Ship-ilovskikh D.A., Dmitriev M.V., Zvereva O.V., Silaichev P.S., Igidov N.M., Shipilovskikh S.A. Decyclization of Substituted 2-[2-Oxofuran-3(2H)-ylidene)furan-2-carbohydrazides by the Action of Alcohols and Analgesic Activity of the Obtained Compounds. Russ. J. Gen. Chem. 2023. V. 93. N 2. P. 253-262. DOI: 10.1134/S1070363223020044.
Denisova E.I., Lipin D.V., Parkhoma K.Yu., Devyatkin I.O., Shipilovskikh D.A., Chashchina S.V., Makhmudov R.R., Igidov N.M., Shipilovskikh S.A. Synthesis, Intramolecular Cyclization, and Antinociceptive Activity of Substituted 2-[2-(4-Nitrobenzoyl)hydrazinylidene]-4-oxobut-2-enoic Acids. Russ. J. Org. Chem. 2021. V. 57. N 12. P. 1955-1960. DOI: 10.1134/S1070428021120083.
Siutkina A.I., Sharavyeva Yu.O., Chashchina S.V., Shipilovskikh S.A., Igidov N.M. Synthesis and anti-inflammatory activity of N′-substituted 2-[2-(diarylmethylene)hydrazinyl]-5,5-dimethyl-4-oxohex-2-enehydrazides. Izv. AN Ser. Khim. 2022. V. 71. N 3. P. 496-501 (in Russian). DOI: 10.1007/s11172-022-3439-9.
Igidov S.N., Turyshev A.Yu., Chashchina S.V., Ship-ilovskikh D.A., Chernov I.N., Zvereva O.V., Silaichev P.S., Igidov N.M., Shipilovskikh S.A. Synthesis and anti-inflammatory activity of N-arylamides of 4-aryl- and 4-(thiophen-2-yl)-2-[2-(furan-2-carbonyl)hydrazono]-4-oxobutanoic acids. Izv. AN Ser. Khim. 2023. V. 72. N 9. P. 2241-2248 (in Russian). DOI: 10.1007/s11172-023-4021-9.
Lipin D.V., Denisova E.I., Shipilovskikh D.A., Makhmudov R.R., Igidov N.M., Shipilovskikh S.A. Synthesis, Intramolecular Cyclization, and Anti-inflammatory Activity of Substituted 2-[2-(4-R-Benzoyl)hydrazinylidene]-4-oxobutanoic Acids. Russ. J. Org. Chem. 2022. V. 58. N 12. P. 1759-1768. DOI: 10.1134/S1070428022120041.
Gorbunova I.A., Shadrin V.M., Pulina N.A., Novikova V.V., Dubrovina S.S., Shipilovskikh D.A., Shipilovskikh S.A. Synthesis and Antibacterial Activity of 4-Oxo-2-thienylaminobut-2-enoic Acids. Russ. J. Gen. Chem. 2023. V. 93. N 1. P. 8-15. DOI: 10.1134/S1070363223010024.
Rogova A., Gorbunova I.A., Karpov T.E., Sidorov R.Yu., Rubtsov A.E., Shipilovskikh D.A., Muslimov A.R., Zyuzin M.V., Timin A.S., Shipilovskikh S.A. Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma. Eur. J. Med. Chem. 2023. V. 254. P. 115325. DOI: 10.1016/j.ejmech.2023.115325.
Gunina E., Timofeeva M., Kenzhebaeva Yu.A., Bachinin S., Gorbunova I.A., Shipilovskikh D.A., Milichko V.A., Shipilovskikh S.A. Thiophene-based thin films with tunable red photoluminescence. Photonics Nanostruct. 2023. V. 56. P. 101168. DOI: 10.1016/j.photonics.2023.101168.
Gorbunova I.A., Timofeeva M., Gunina E., Sharavyeva Yu.O., Parkhoma K.Yu., Shipilovskikh D.A., Shipilov-skikh S.A. Selfassembly of thiophene-based luminescent thin films on flexible substrates. Photonics Nanostruct. 2024. V. 58. P. 101220. DOI: 10.1016/j.photonics.2023.101220.
Gorbunova I.A., Okoneshnikova E.A., Makhmudov R.R., Shipilovskikh D.A., Shadrin V.M., Silaichev P.S., Shipilovskikh S.A. Synthesis and antinociceptive activity of N-substituted 4-aryl-2-[(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino]4-oxobut-2-enamides. Izv. AN Ser. Khim. 2023. V. 72. N 8. P. 1905-1912 (in Russian). DOI: 10.1007/s11172-023-3975-y.
Gorbunova I.A., Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Shadrin V.M., Pulina N.A., Ship-ilovskikh S.A. Synthesis and Antinociceptive Activity of Substituted 2-(3-Cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2-ylamino)-4-oxobut-2-enoates. Russ. J. Gen. Chem. 2022. V. 92. N 10. P. 1899-1905. DOI: 10.1134/S1070363222100048.
Sharavyeva Yu.O., Siutkina A.I., Chashchina S.V., Novikova V.V., Makhmudov R.R., Shipilovskikh S.A. Synthesis, analgesic and antimicrobial activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxo-4-phenylbut-2-enoates. Izv. AN Ser. Khim. 2022. V. 71. N 3. P. 538-542 (in Russian). DOI: 10.1007/s11172-022-3445-y.
Eddy N.B., Leimbach D.J. Synthetic analgesics. II. Dithi-enylbutenyl-and dithienylbutylamines. J. Pharmacol. Exp. Ther. 1953. V. 107. N 3. P. 385.
Mironov A.N. Guidelines for conducting preclinical studies of medicinal substances. M.: Grif and K. 2012. 509 p. (in Russian).
Pershin G.N. Methods of experimental chemotherapy. M.: Medicine. 1971. 109 p. (in Russian).
Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons at a single exposure. M.: Medicine. 1977. 196 p. (in Russian).
Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. L.: Medgiz. 1963. 146 p. (in Russian).
Verbić T., Drakulić B., Zloh M., Pecelj J., Popović G., Juranić I. An LFER study of the protolytic equilibria of 4-aryl-2,4-dioxobutanoic acids in aqueous solutions. J. Serbian Chem. Soc. 2007. V. 72. N 12. P. 1201-1216. DOI: 10.2298/ jsc0712201v.
Gewald K., Schinke E., Böttcher H. Heterocyclen aus CH‐aciden Nitrilen, VIII. 2‐Amino‐thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Schwefel. Chem. Ber. 2006. V. 99. N 1. P. 94-100. DOI: 10.1002/cber.19660990116.
