Synthesis and antinociceptive activity of 2,2’-(1,4-phenylene)bis[3-aryl-2-azaspiro[3.5]nonan-1-ones]

Over the years, azetidin-2-ones, or β-lactams, have received a lot of attention from scientists as potential drug candidates due to their diverse biological activity. Spiro-β-lactams also exhibit biological activity; therefore, it is of interest to synthesize and study the properties of new compounds belonging to this class. The study aims to examine the antinociceptive activity of several synthesized bis(spirolactams), specifically 2,2’-(1,4-phenylene)bis[3-aryl-2azaspiro[3.5]nonan-1-ones]. These bis(spiroazetidine-2-ones) were obtained in the interaction of a twofold excess of the Reformatsky reagent, derived from methyl 1-bromocyclohexane carboxylate and zinc, with N,N-(1,4-phenyle- ne)bis(1-arylmethanimines) by means of boiling them in a 10:1 mixture of toluene and hexamethylphosphorictriamide for four hours. Bis(spiro-β-lactams) on the basis of diimines derived from p-phenylenediamine, 2-methoxybenzaldehyde, p-tolualdehyde, and 3-bromobenzoic aldehyde were synthesized for the first time. The composition and structure of the previously undescribed products were established using IR, ^[1]H, and ¹³C NMR spectroscopy and elemental analysis. The antinociceptive activity of the obtained compounds was studied on outbred white mice of both sexes via the hot plate test with an intraperitoneal injection. The effect was estimated two hours after administration. Several synthesized compounds were found to exhibit antinociceptive activity at or above the level of the comparator product – metamizole sodium. Nerve endings can be considered the target of the antinociceptive activity of examined substances since under the effect of these substances, no signs of central action are observed in the behavior of animals. Thus, the conducted studies showed the promise of further search for biologically active substances among the compounds of this series.

1. Dardoize F., Moreau J.-L., Gaudemar M. Sur la reactivite des metaliquesmediaires de Reformatsky vis-a-vis de la fonction imine // Comptesrendus de l’Académie des Sciences. 1969. Vol. 268, nu. 25. P. 2228–2230.

2. Kirillov N.F., Shchepin V.V. Reaction with azomethines or azines of Reformatsky reagents prepared from methyl 1-bromocycloalkanoates and zinc // Russian Journal of General Chemistry. 2005. Vol. 75, no. 4. P. 590–592. DOI: 10.1007/s11176-005-0277-z.

3. Shchepin V.V., Melekhin V.S., Kirillov N.F. Reformatsky reaction of methyl 1-bromocyclobutane- and 1-bromocycloheptanecarboxylates with Schiff bases // Russian Journal of Organic Chemistry. 2007. Vol. 43, no. 11. P. 1632–1634. DOI: 10.1134/S1070428007110085.

4. Nikiforova E.A., Baibarodskikh D.V., Zverev D.P., Dmitriev M.V., Kirillov N.F. Reaction of 2- and 4-(Arylmethylideneamino)phenols with Methyl 1-Bromocyclohexanecarboxylate and Zinc // Russian Journal of Organic Chemistry. 2021. Vol. 57, no. 8. P. 1275–1280. DOI: 10.1134/S1070428021080066.

5. Kirillov N.F., Nikiforova E.A., Baibarodskikh D.V., Zakharova T.A., Govorushkin L.S. Synthesis of new bis(spiro-β-lactams) via interaction of methyl 1-bromocycloalcanecarboxylates with zinc and N,N′bis(arylmethylidene)benzidines // Journal of Chemistry. 2019. P. 7496512. DOI: 10.1155/2019/7496512.

6. Jarrahpour A., Jowkar Z., Haghighijoo Z., Heiran R., Rad J.A., Sinou V., et al. Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiroβ-lactam-isatin hybrids // Medicinal Chemistry Research. 2022. Vol. 31, no. 6. P. 1026–1034. DOI: 10.1007/s00044-022-02898-8.

7. Bari S.S., Bhalla A. Spirocyclic β-lactams: synthesis and biological evaluation of novel heterocycles // Heterocyclic scaffolds I: ß-lactams / ed. B.K. Banik. Berlin – Heidelberg: Springer, 2010. P. 49–99. DOI: 10.1007/7081_2009_8.

8. Nikiforova E.A., Makhmudov R.R., Rudin A.A., Dmitriev M.V., Baibarodskikh D.V., Kirillov N.F., et al. Reaction of N′-(arylmethylidene)-2-oxo-2H-chrome- ne-3-carbohydrazides with methyl 1-bromocycloalkanecarboxylates and zinc // Russian Journal of General Chemistry. 2021. Vol. 91, no. 1. P. 64–71. DOI: 10.1134/S1070363221010060.

9. Alborz M., Pournejati R., Rad J.A., Jarrahpour A., Karbalaei-Heidari H.R., Brunel J.M., et al. Design and preparation of β-lactam derivatives bearing phenanthrenimidazole as cytotoxic agents // ChemistrySelect. 2022. Vol. 7, no. 29. P. e202202306. DOI: 10.1002/slct.202202306.

10. Ranjbari S., Behzadi M., Sepehri S., Aseman M.D., Jarrahpour A., Mohkam M., et al. Investigations of antiproliferative and antioxidant activity of β-lactam morpholino-1,3,5-triazine hybrids // Bioorganic & Medicinal Chemistry. 2020. Vol. 28, no. 8. P. 115408. DOI: 10.1016/j.bmc.2020.115408.

11. Heiran R., Sepehri S., Jarrahpour A., Digiorgio C., Douafer H., Brunel J.M., et al. Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped β-lactam derivatives // Bioorganic Chemistry. 2020. Vol. 102. P. 104091. DOI: 10.1016/j.bioorg.2020.104091.

12. Hosseyni S., Jarrahpour A. Recent advances in β-lactam synthesis // Organic & Biomolecular Chemistry. 2018. Vol. 16, no. 38. P. 6840–6852. DOI: 10.1039/c8ob01833b.

13. Jarrahpour A., Rezaei S., Sinou V., Latour C., Brunel J.M. Synthesis of some novel 3-spiro monocyclic β-lactams and their antibacterial and antifungal investigations // Iranian Journal of Science and Technology, Transaction A: Science. 2017. Vol. 41, no. 2. P. 337–342. DOI: 10.1007/s40995-016-0033-8.

14. Rad J.A., Jarrahpour A., Ersanlı C.C., Atioğlu Z., Akkurt M., Turos E. Synthesis of some novel inde- no[1,2-b]quinoxalin spiro-β-lactam conjugates // Tetrahedron. 2017. Vol. 73, no. 8. P. 1135–1142. DOI: 10.1016/j.tet.2017.01.009.

15. Jarrahpour A., Ebrahimi E., De Clereq E., Sinou V., Latour C., Bouktab L.D., et al. Synthesis of mono-, bis-spiro- and dispiro-β-lactams and evaluation of their antimalarial activities // Tetrahedron. 2011. Vol. 67, no. 45. P. 8699–8704. DOI: 10.1016/j.tet.2011.09.041.

16. Sek D., Siwy M., Bijak K., Grucela-Zajac M., Malecki G., Smolarek K., et al. Comparative studies of structural, thermal, optical, and electrochemical properties of azines with different end groups with their azomethine analogues toward application in (opto)electronics // Journal of Physical Chemistry A. 2013. Vol. 117, no. 40. P. 10320–10332. DOI: 10.1021/jp407623u.

17. Nikiforova E.A., Baibarodskikh D.V., Kirillov N.F., Glavatskikh L.A. Reformatsky reaction of methyl 1-bromocyclohexanecarboxylate with N,N′-(1,4-phenylene) bis(1-arylmethanimines) // Russian Journal of Organic Chemistry. 2020. Vol. 56, no. 6. P. 1029–1033. DOI: 10.1134/S107042802006010X.

18. Eddy N.B., Leimbach D.J. Synthetic analgesics. II. Dithie-nylbutenyl- and dithienylbutylamines // Journal of Pharmacology and Experimental Therapeutics. 1953. Vol. 107, no. 3. P. 385–393.

19. Sigidin Ya.A., Shvarts G.Ya., Arzamastsev A.P., Liberman S.S. Drug therapy of the inflammatory process: Experimental and clinical pharmacology of anti-inflammatory drugs. Moscow: Meditsina; 1988, 238 p. (In Russian).

20. Belen’kii M.L. Elements of quantitative assessment of pharmacological effect. Leningrad: Medgiz; 1963, 152 p. (In Russian).