Synthesis and antioxidant properties of N -substituted aminomethyl derivatives of 2-isobornylphenol
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1971
Synthesis and antioxidant properties of N-substituted aminomethyl derivatives of 2-isobornylphenol E. V. Buravleva and O. G. Shevchenkob aInstitute
of Chemistry, Komi Scientific Centre, Ural Branch of the Russian Academy of Sciences, 48 ul. Pervomayskaya, 167000 Syktyvkar, Russian Federation. Fax: +7 (821 2) 21 9916. E-mail: [email protected] bInstitute of Biology, Komi Scientific Centre, Ural Branch of the Russian Academy of Sciences, 28 ul. Kommunisticheskaya, 167982 Syktyvkar, Russian Federation. Fax: +7 (821 2) 24 0163 A series of 2-isobornylphenol derivatives containing aminomethyl groups either at ortho(monoderivatives) or ortho- and para-positions (bis-derivatives) relative to the hydroxy group of phenol moiety was synthesized. Antioxidant properties of the obtained compounds were comparatively evaluated using in vitro models. It was demonstrated that Mannich bases containing an n-octylaminomethyl group are significantly exceeding both starting 2-isobornylphenol and the standard antioxidant, 2,6-di-tert-butyl-4-methylphenol, by their ability to inhibit H2O2-induced erythrocyte hemolysis. Key words: aminomethylation, Mannich bases, antioxidant activity, membrane-protective activity, erythrocytes, oxidative hemolysis, aminomethyl derivatives of 2-isobornylphenol.
Terpenylphenols1 are a special class of natural and semisynthetic compounds that combine phenolic and terpene2 moieties in their molecules. They exhibit a wide range of biological activity towards warm-blooded organisms1 and may be an attractive platform for the synthesis of new derivatives. In particular, phenols bearing an isobornyl (bicyclo[2.2.1]heptyl) moiety are already used in medicine.3 An introduction of the aminomethyl group into organic molecules is often employed in the drug design and synthesis and, in particular, for the modification of phenolic compounds.4 Antioxidant properties of aminomethyl derivatives of such natural phenols as thymol,5 quercetin,6 and mangostins7 set them apart from their precursors. In the case of certain Mannich bases obtained from synthetic terpenylphenols, an increased antioxidant activity (AOA) was also observed, while the highest AOA was exhibited by the phenols containing a bicyclic terpene moiety and an aminomethyl substituent with a secondary amino group.8—10 This work was aimed at the synthesis of Mannich bases based on one of the simplest and synthetically available terpenylphenols, viz. 2-isobornylphenol (1),11 the evaluation of AOA of the synthesized compounds on different in vitro models, and revealing the structure—activity relationship. Results and Discussion Scheme 1 shows the synthesis of derivatives 2—11 from compound 1. Mixtures of mono- (2, 4, 6, and 8) and di-
aminomethylation (3, 5, 7, and 9) products with tertiary amino groups were obtained via the reaction of phenol 1 with paraform (2.5 equiv.) and the corresponding secondary amine. Pure products were isolated using column chromatography on silica gel. Transamination of dimethylaminomethyl derivatives 2 and 3 afforded the correspo
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