Synthesis and biological activity evaluation in silico of bis(4-hydroxy-6H-1,3-oxazin-6-one) derivatives and the products of their alcoholysis

Introduction. According to research data, 1,3-oxazines are pharmacologically active substances, as well as the substrates for the synthesis of heterocyclic and acyclic compounds. However, bis(1,3-oxazin-6-one) derivatives are little studied class of compounds, which makes their research a promising direction for the development of modern synthetic chemistry and pharmacy. The aim of this work is to obtain bis(4-hydroxy-6H-1,3-oxazin-6-ones), study their alcoholysis reaction, prove the structure of the obtained products and evaluate their pharmacological potential in silico.

Methods. The reflux of isophthalic acid diamide with a twofold excess of substituted malonyl chloride in 1,2-dichloroethane for 15 hours led to the production of bis(4-hydroxy-6H-1,3-oxazin-6-ones) (1, 2). As a result of their reflux with absolute ethanol for 5 hours acyclic esters of malonamic acids (3, 4) formed. The structure of the obtained compounds was proved by ¹H and ¹³C NMR spectroscopy. The prediction of biological activity was carried out using the GUSAR and PASS online web-resources.

Results. The yields of compounds 1-4 were 90%, 90%, 93%, 89%, respectively, depending on the nature of the substituent at position C₅ of the oxazine cycle. According to the in silico assessment of biological activity, bis(1,3-oxazine-6-ones) exhibited high probability of antitumor activity, while ethyl esters of malonamic acids showed promising anxiolytic, antieczematous, fibrinolytic activities.

Conclusions. New bridging 1,3-oxazin-6-ones were synthesized. The reaction of their cleavage by absolute ethanol to malonamic acid esters was studied. The potential biological activity was predicted in silico.