N-[2-(5,5-Dimethyl-1,3-dioxane-2-yl)ethyl]amino acids: Their synthesis, anti-inflammatory evaluation and QSAR analysis

Developing novel anti-inflammatory drugs is increasingly important in modern pharmaceutical industry. In this work, the reactions of both amino acids and their methylesters with 3-(5,5-dimethyl-1,3-dioxane-2-yl)propanal (2) were performed to either directly provide the goal products N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acids (4a–s) in 9–65% yields or provide the intermediates N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acid methylesters (3a–s) in 78–87% yields. The saponification of 3a–s provided 4a–s in 80–89% yields. Using a xylene-induced ear edema model, the anti-inflammatory activities of these newly synthesized anti-inflammatory agents were evaluated. The results indicated that comparing to the vehicle control 17 out of 4a–s significantly inhibited the development of inflammation in mice (p < 0.01). In particular, eight out of 4a–s exhibited an even higher anti-inflammatory activity than the standard reference drug aspirin (p < 0.05–0.01). A QSAR analysis was performed by use of the molecular descriptors generated from e-dragon software. The predictive accuracy of the established QSAR model implies that it may be promising for screening the new derivatives of 2-position amino acid substituted 1,3-dioxanes as potential anti-inflammatory agents.

The synthesis route of N-[2-(5,5-dimethyl-1,3-dioxane-2-yl)ethyl]amino acids (4a–s).Figure optionsDownload as PowerPoint slide