The synthesis of spiro-2-oxindole-derivative imides of pyrrolidine-3,4-dicarboxylic acid with biogenous sulfur amino acid residues and their antihypoxic activity

R. G. Redkin

Abstract


Modification of the spiro-2-oxindole skeleton due to introduction of pharmacophores of the known biologically active substances is a productive way for searching and creating new biologically active molecules with the non-planar structure.
Aim. To synthesize spiro-2-oxindole derivatives of pyrrolidine-3,4-dicarboxylic acid imides with residues of biogenic sulfur-containing α-amino acids and study their anti-hypoxic activity.
Results and discussion. Using a three-component one-pot reaction of isatin with sulfur-containing α-amino acids and maleimides a number of new spiro-imides, including 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole-3,2(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones 6a-s, was synthesized with the yields of 55-92 %. The structure and the composition of the compounds synthesized are consistent with the results of X-Ray, elemental analysis, mass and NMR-spectra. It was found that only two of the eight possible enantiomers of spiro-imides were formed. Spiro-imide with a methionine residue in the dose of 10 mg/kg was the most active, and increased the life expectancy in rats with respect to the control group by 33.7 % on average. Against the background of acute asphyxia the preventive administration of piro-imide with a methionine residue in the dose of 5 mg/kg was the most effective; it increased the duration of the bioelectric activity of the heart by 12.1 %.                                       Experimental part. The synthesis of compounds was performed using a three-component condensation in the alcoholic-aqueous medium. The methods of X-Ray, 1H, 13C NMR-spectroscopy, and mass spectrometry were used. The study of the antihypoxic activity was carried out on models of acute normobaric hypoxic hypoxia with hypercapnia and acute asphyxia in male rats of the Wistar line. The antihypoxic effect was assessed by the bioelectric activity of the heart. Conclusions. An effective approach to the synthesis of 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole- 3,2’(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones has been developed; among them a compound with a moderate antihypoxic activity has been found.


Keywords


spiro[pyrrolidine-3,2’-oxindole]; multicomponent reactions; antihypoxic activity; bioelectric activity of the heart

References


Ball–Jones, N. R. Strategies for the enantioselective synthesis of spirooxindoles / N. R. Ball–Jones, J. J. Badillo, A. K. Franz // Org. Biomol. Chem. – 2012. – Vol. 10, Issue 27. – P. 5165. doi : 10.1039/c2ob25184a.

Murugan, R. Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione

and rhodanine derivatives / R. Murugan, S. Anbazhagan, S. S. Narayanan // Eur. J. of Med. Chem. – 2009. – Vol. 44, Issue 8. – P. 3272–3279. doi :

1016/j.ejmech.2010.04.021.

A facile 1,3–dipolar cycloaddition of azomethine ylides to 2–arylidene–1,3–indanediones: synthesis of dispiro–oxindolylpyrrolothiazoles and

their antimycobacterial evaluation / S. U. Maheswari, K. Balamurugan, S. Perumal et al. // Bioorg. Med. Chem. Lett. – 2010. – Vol. 20, Issue 24. –

P. 7278–7282. doi : 10.1016/j.bmcl.2010.10.080.

Chemistry of Indoles Carrying a Basic Function, Part 31 Synthesis of Spiro[cyclopropane–1,3’[3H]indol]–2’(1’H)–ones with Antihypoxic Effects

/ I. Moldvai, E. Gács–Baitz, M. Balázs et al. // Arch. Pharm. Pharm. Med. Chem. – 1996. – Vol. 329, Issue 12. – P. 541–549. doi : 10.1002/

ardp.19963291206.

Prenatal developmental toxicity study of the pyridolindole antioxidant SMe1EC2 in rats / E. Ujházy, M. Dubovický, V. Ponechalová et al. // Neuro

Endocrinol. Lett. – 2008. – Vol. 29. – P. 639–643.

Цубанова, Н. А. Антидепресивні властивості спіроциклічного похідного оксіндолу / Н. А. Цубанова, С. Ю. Штриголь, Р. Г. Редькін //

Клінічна фармація. – 2011. – № 15. – С. 56–60.

Скринiнг in silico потенцiйних iнгiбiторiв 11–гiдроксистероїддегiдрогенази / В. В. Лiпсон, В. В. Бородiна, Р. Г. Редькiн та ін. // Проблеми

ендокринної патол. – 2016. – № 1. – С. 56–62.

Alvarez–Carreño, C. Norvaline and norleucine may have been more abundant protein components during early stages of cell evolution / C. Alvarez–

Carreño, A. Becerra, A. Lazcano // Orig. Life Evol. Biosph. – 2013. – Vol. 43, Issue 4–5. – P. 363–375. doi : 10.1007/s11084–013–9344–3.

Bigelow, D. J. Thioredoxin–dependent redox regulation of cellular signaling and stress response through reversible oxidation of methionines /

D. J. Bigelow, T. C. Squier // Mol. Biosyst. – 2011. – Vol. 7, Issue 7. – P. 2101. doi : 10.1039/c1mb05081h.

Segovia, G. Effects of aging on the interaction between glutamate, dopamine, and GABA in striatum and nucleus accumbens of the awake rat / G. Segovia, A. Del Arco, F. Mora // J. Neurochem. – 2002. – Vol. 73, Issue 5. – P. 2063–2072. doi : 10.1046/j.1471–4159.1999.02063.x.

Discovery of a factor Xa inhibitor (3R,4R)–1–(2,2–difluoro–ethyl)–pyrrolidine–3,4–dicarboxylic acid 3–[(5–chloro–pyridin–2–yl)–amide] 4–

[[2–fluoro–4–(2–oxo–2H–pyridin–1–yl)–phenyl]–amide] as a clinical candidate / L. Anselm, D. W. Banner, J. Benz et al. // Bioorg. Med. Chem.

Lett. – 2010. – Vol. 20, Issue 17. – P. 5313–5319. doi : 10.1016/j.bmcl.2010.06.126.

Molecular diversity of spirooxindoles. Synthesis and biological activity / T. L. Pavlovska, R. G. Redkin, V. V. Lipson, D. V. Atamanuk // Mol. Divers. –

– Vol. 20, Issue 1. – P. 299–344. doi : 10.1007/s11030–015–9629–8.

Synthesis and chemical properties of new derivatives of 3a,6a–dihydro–2H–spiro–[indole–3,1–pyrrolo[3,4–c]pyrrole]–2,4,6(1H,3H,5H)trione /

T. L. Pavlovskaya, R. G. Redkin, F. G. Yaremenko et al. // Chem. Heterocycl. Comp. – 2013. – Vol. 49, Issue 6. – P. 882–896. doi : 10.1007/s10593–

–1322–1.

Zai–Qun, L. Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction for Constructing Thiazolines and Imidazolines / Liu Zai–

Qun // Current Organic Synthesis. – 2015. – Vol. 12, Issue 1. – P. 20–60. doi : 10.2174/1570179411999141112144441.

Зефиров, Ю. В. Ван–дер–Ваальсовы радиусы и их применение в кристаллохимии / Ю. В. Зефиров // Кристаллография. – 1997. – С. 936–958.

Arome, D. The importance of toxicity testing / D. Arome, E. Chinedu // J. Pharm. Bio Sci. – 2013. – Vol. 4. – P. 146–148.

Sheldrick, G. M. A short history of SHELX / G. M. Sheldrick // Acta Crystallogr. A. – 2008. – Vol. 64. – P. 112–122.

Rumyantseva, S. A. Antioxidant Treatment of Ischemic Brain Lesions / S. A. Rumyantseva, A. I. Fedin, O. N. Sokhova // Neuroscie. and Behavioral

Physiol. – 2012. – Vol. 42, Issue 8. – P. 842–845. doi : 10.1007/s11055–012–9646–3.


GOST Style Citations


1. Ball–Jones, N. R., Badillo, J. J., Franz, A. K. (2012). Strategies for the enantioselective synthesis of spirooxindoles. Organic & Biomolecular Chemistry,
10 (27), 5165. doi: 10.1039/c2ob25184a.

2. Murugan, R., Anbazhagan, S., Narayanan, S. S. (2010). Corrigendum to “Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines
through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives ” [European Journal of Medicinal Chemistry 44 3272–3279].
European Journal of Medicinal Chemistry, 45 (8), 3518–3518. doi: 10.1016/j.ejmech.2010.04.021.

3. Maheswari, S. U., Balamurugan, K., Perumal, S., Yogeeswari, P., Sriram, D. (2010). A facile 1,3–dipolar cycloaddition of azomethine ylides to
2–arylidene–1,3–indanediones: Synthesis of dispiro–oxindolylpyrrolothiazoles and their antimycobacterial evaluation. Bioorganic & Medicinal
Chemistry Letters, 20 (24), 7278–7282. doi: 10.1016/j.bmcl.2010.10.080.

4. Moldvai, I., Gács–Baitz, E., Balázs, M., Incze, M., Szántay, C. (1996). Chemistry of Indoles Carrying a Basic Function, Part 31 Synthesis of Spiro[cyclopropane– 1,3’[3H]indol]–2’(1’H)–ones with Antihypoxic Effects. Archiv Der Pharmazie, 329 (12), 541–549. doi: 10.1002/ardp.19963291206.

5. Ujházy, E., Dubovický, M., Ponechalová, V. et al (2008). Prenatal developmental toxicity study of the pyridolindole antioxidant SMe1EC2 in rats.
Neuro Endocrinol Lett., 29, 639–643.

6. Tsubanova, N. A., Strygo,l S. Yu., Redkin R. G.(2011). Klinichna Pharmatsia – Clinical Pharmacy, 15 (1), 56–60.

7. Lipson, V. V., Borodina, V. V., Redkin, R. G. et al. (2016). Problemy endokrynnoi patolohii, 1, 56–62.

8. Alvarez–Carreño, C., Becerra, A., Lazcano, A. (2013). Norvaline and Norleucine May Have Been More Abundant Protein Components during Early
Stages of Cell Evolution. Origins of Life and Evolution of Biospheres, 43 (4–5), 363–375. doi: 10.1007/s11084–013–9344–3.

9. Bigelow, D. J., Squier, T. C. (2011). Thioredoxin–dependent redox regulation of cellular signaling and stress response through reversible oxidation
of methionines. Molecular BioSystems, 7 (7), 2101. doi: 10.1039/c1mb05081h.

10. Effects of Aging on the Interaction Between Glutamate, Dopamine, and GABA in Striatum and Nucleus Accumbens of the Awake Rat. (2002).
Journal of Neurochemistry, 73 (5), 2063–2072. doi: 10.1046/j.1471–4159.1999.02063.x.

11. Anselm, L., Banner, D. W., Benz, J., Groebke Zbinden, K., Himber, J., Hilpert, H., Haap, W. (2010). Discovery of a factor Xa inhibitor (3R,4R)–1–(2,2– difluoro–ethyl)–pyrrolidine–3,4–dicarboxylic acid 3–[(5–chloro–pyridin–2–yl)–amide] 4–{[2–fluoro–4–(2–oxo–2H–pyridin–1–yl)–phenyl]–amide} as
a clinical candidate. Bioorganic & Medicinal Chemistry Letters, 20 (17), 5313–5319. doi: 10.1016/j.bmcl.2010.06.126.

12. Pavlovska, T. L., Redkin, R. G., Lipson, V. V., Atamanuk, D. V. (2015). Molecular diversity of spirooxindoles. Synthesis and biological activity. Molecular
Diversity, 20 (1), 299–344. doi: 10.1007/s11030–015–9629–8.

13. Pavlovskaya, T. L., Redkin, R. G., Yaremenko, F. G. et al. (2013). Synthesis and chemical properties of new derivatives of 3a,6a–dihydro–2H–spiro– [indole–3,1–pyrrolo[3,4–c]pyrrole]–2,4,6(1H,3H,5H)trione. Chem Heterocycl Comp., 49 (6), 882–896. doi: 10.1007/s10593–013–1322–1.

14. Liu, Z.–Q. (2015). Two Neglected Multicomponent Reactions: Asinger and Groebke Reaction for Constructing Thiazolines and Imidazolines. Current
Organic Synthesis, 12 (1), 20–60. doi: 10.2174/1570179411999141112144441.

15. Zefirov, Yu. V. (1997). Kristallographiia – Crystallography Reports, 42 (5), 936–958.

16. Arome, D., Chinedu, E. (2013). The importance of toxicity testing. Pharm. Bio Sci., 4, 146–148.

17. Sheldrick, G. M. (2008). A short history of SHELX. Acta Crystallographica. Section A, 64, 112–122.

18. Rumyantseva, S. A., Fedin, A. I., Sokhova, O. N. (2012). Antioxidant Treatment of Ischemic Brain Lesions. Neuroscience and Behavioral Physiology,
42 (8), 842–845. doi: 10.1007/s11055–012–9646–3.





DOI: https://doi.org/10.24959/ophcj.17.914

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)