One-Step Synthesis of a Novel N-Acylmalonamic Acid Ester and Its Potential as an Antiviral Agent

N-acylmalonamic acid derivatives are important structural fragments of a wide range of biologically active compounds. The advantage of this chemical system is its one-step formation using bis(4-hydroxy-6H-1,3-oxazine-6-ones) and oxygen-containing nucleophiles. The aim of this study was to develop a method of the synthesis and subsequent in silico screening of the antiviral activity of a novel N-acylmalonamic acid ester.

The target compound was obtained by treating 2,2’-(benzene-1,4-diyl)bis(4-hydroxy-5-phenyl-6H-1,3-oxazine-6-one) with methanol under reflux for 5 hours. The structure of the synthesized product was unambiguously proved by NMR spectroscopy on ¹H and ¹³C nuclei. The prediction of biological activity was performed using the online platforms GUSAR, PASS, and AntiCOVID; molecular docking was carried out in the SwissDock software package with a focus on interaction with the main protease of the SARS-CoV-2 virus.

The yield of the target ester was 79%. The results of the in silico analysis indicate that the compound has the potential to exhibit antiviral activity against influenza A virus and SARS-CoV-2. Quantitative assessment of the binding affinity of the molecule toward the SARS-CoV-2 protease demonstrated that the synthesized product is only slightly inferior to the reference drug.

Thus, in the course of the work, a new ester of N-acylmalonamic acid was successfully obtained with a high yield. Its structure was reliably proven by a spectral method. The data of computer screening allow the synthesized compound to be considered as a promising candidate for further development as an antiviral agent.