Exploring uracil derivatives: synthesis, crystal structure insights, and antibacterial activity†

Abstract

As one of four nucleobases of RNA, uracil and its analogues represent an important class of bioactive pyrimidine derivatives. Their molecular arrangements in the solid state can be explored from the crystal engineering approach to obtain an understanding of structure–bioactivity correlations. In the present study, a series of uracil derivatives (compounds 1–4) was synthesized and fully characterized. The effect of the functionalization of the uracil core with different –NCHN(CH₃)₂, –CH₃, –Cl, S, –NH₂, and –CH₂–COOH groups on stability, solubility, and antibacterial activity was investigated. The single-crystal structures of these compounds show that the hydrogen bonds formed by distinct synthons (R²₂(8), R⁴₄(12), C¹₁(6)) contribute to framework stability. The presence of water molecules in the lattice is an important feature, as they provide additional H-bonding interactions that influence lattice energy and solubility. Lattice energy minimization, Hirshfeld surface analysis, and 2D fingerprint plots were employed to investigate intermolecular interactions and the stability of the obtained uracil derivatives, particularly the effect of functional groups. Although all compounds exhibit antibacterial behavior, the derivatives with small polar functional groups revealed an enhanced activity against Gram-negative bacteria, while the compounds with moderately polar substituents are more active against Gram-positive bacteria. The established discussions expand the comprehension of uracil chemistry and highlight the relationship between crystal structure and the resulting properties of the compounds, thus contributing to the rational development of new antibacterial agents.