Spiro Derivatives of 1,10b-dihydro-5 H -pyrazolo[1,5- c ][1,3]-benzoxazines and their Antimicrobial, Anti-Inflammatory,
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Spiro derivatives of 1,10b-dihydro-5H-pyrazolo[1,5-c][1,3]benzoxazines and their antimicrobial, anti-inflammatory, and antioxidant activity Lidiya Z. Mandzyuk1, Vasyl S. Matiychuk2, Taras I. Chaban3, Olesya V. Bodnarchuk1, Julia E. Matiychuk3, Mykola D. Obushak2* 1
Ivano-Frankivsk National Medical University, 2 Halyt'ska St., Ivano-Frankivsk 76018, Ukraine 2 Ivan Franko National University of Lviv 6 Kyryla i Mefodia St., Lviv, 79005, Ukraine; e-mail: [email protected] 3 Danylo Halytsky Lviv National Medical University, 69 Pekarska St., Lviv 79010, Ukraine Translated from Khimiya Geterotsiklicheskikh Soedinenii, 2020, 56(11), 1485–1490
Submitted February 29, 2020 Accepted after revision May 20, 2020
The reaction of 2-(3-aryl-4,5-dihydro-1H-pyrazol-5-yl)phenols with cyclopentanone, cyclohexanone, or 4-methylcyclohexanone gave spiro derivatives of 1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazines. The antimicrobial, anti-inflammatory, and antioxidant activities of these compounds were studied. A compound with a high antimicrobial activity against S. aureus ATCC 43300, together with compounds possessing an anti-inflammatory effect superior to the reference drug diclofenac, as well as high antioxidant activity, were identified. Keywords: 1,3-benzoxazines, chalcones, 1,3-oxazines, pyrazolines, pyrazolo[1,5-c][1,3]benzoxazines, anti-inflammatory activity, antimicrobial activity, antioxidant activity.
Condensed nitrogen-containing heterocyclic compounds play an important role in organic and medicinal chemistry, since they possess various types of biological activity and are used as drugs.1 Expanding on our studies2 on the synthesis and biological activity of condensed nitrogen-containing heterocycles, in this work we studied the approach to the synthesis of new spiro derivatives of 1,10b-dihydropyrazolo[1,5-c][1,3]benzoxazines and their bioactivity. A preparative method for the construction of this heterocyclic system is the reaction of 2-(3-aryl-4,5-dihydro-1H-pyrazol5-yl)phenols with carbonyl compounds.3–7 Expansion of the scope of this method remains urgent. Little is known about the biological activity of this class of compounds. They have been shown to be effective antagonists of 5-HT2B serotonin receptors.5 It has also been reported that pyrazolo[1,5-c][1,3]benzoxazine derivatives have a minor antimicrobial activity against E. coli, 0009-3122/20/56(11)-1485©2020 Springer Science+Business Media, LLC
P. aeruginosa, S. aureus, and S. pyogenes.7 At the same time, they did not exhibit antifungal properties. We have studied the reaction of pyrazolines 1a–i with cyclopentanone (2), cyclohexanone (3a), and 4-methylcyclohexanone 3b. It was found that heating the reagents in EtOH for 1 h resulted in the formation of the 1,3-oxazine ring, as a result of which compounds 4a–f and 5a–e were obtained (Scheme 1). The obtained spiro derivatives of pyrazolo[1,5-c][1,3]benzoxazines 4a–f and 5a–e are readily soluble on heating in DMF, DMSO, 1,4-dioxane, and MeCN. In the 1H NMR spectra, the pyrazolooxazine fragment CH2 group proto
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