Synthesis and Biological Evaluation of 3,4-Dihydro-3-(3-methylisoxazol-5- yl)-2H-benzo[e][1,3]oxazine Derivatives as Anticancer Agents

Author(s): Ramu Kakkerla*, Srinivas Marri, M.P.S. Murali Krishna, Parusharamulu Molgara, Y.N. Reddy

Journal Name: Letters in Organic Chemistry

Volume 15 , Issue 2 , 2018

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Graphical Abstract:


Background: Cancer is a major health problem worldwide and the major cause of human mortality in the world. The identification of novel structures for effective treatment of cancer is still a major challenge to medicinal chemists. Over the time, important milestones have been achieved in the development of various cancer static drugs for antitumor chemotherapy. Chemotherapy is still highly inadequate, and this necessitates to find novel compounds with potent anticancer activity and minimal or no side effects.

Methods: 5-Amino-3-methyisoxazole 1 was treated with different salicylaldehydes 2a-d refluxing in methanol to get the desired products 2-(3-methylisoxazol)-5-ylimino)methyl)phenols 3a-d. The reduction of these imine intermediates with NaBH4 at room temperature produced the amino phenols 4a-d, which underwent smooth ring closure in the presence of formaldehyde, to give isoxazolyl-1,3- benzoxazine derivatives 5a-d. Compound 5d under Suzuki coupling conditions with different aryl and hetero aryl boronic acids furnished the products 7a-d.

Results: We synthesized the 3,4-dihydro-8-methoxy-3-(3-methylisoxazol-5-yl)-2H-benzo[e][1,3]oxazine derivatives 5a-5d and 7a-7d from readily accessible starting materials in excellent yields. The newly synthesized compounds 5a-5d and 7a-7d were evaluated for in vitro and potent compounds 5b and 7b were screened for in vivo anticancer activity. Compound 5b has shown potential anticancer activity both in vitro and in vivo. Molecular docking studies were also carried out to balance the experimental results.

Conclusion: The structure of all newly synthesized compounds 3-5a-d and 7a-d was confirmed on the basis of IR, 1H NMR, 13C NMR and mass spectral data. Molecular docking studies of compounds 5b and 7b revealed their efficient binding in the hydrophobic pocket in the ATP binding site of EGFR which is consistent with the biological data. Further studies are needed to identify the specific compounds in the series and to develop them as potential anticancer agents.

Keywords: Isoxazolyl-1, 3-benzoxazine, Suzuki-Miyura coupling, anticancer activity, Ehrlich Ascites Carcinoma (EAC), Epidermal Growth Factor Receptor (EGFR).

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Article Details

Year: 2018
Published on: 10 January, 2018
Page: [124 - 132]
Pages: 9
DOI: 10.2174/1570178614666170623121207
Price: $65

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