A New Cu (II) Complex With 1,3-Dimethyl-5-Acetyl-Barbituric Acid: Synthesis, Crystal Structure, DNA/BSA Binding Activities, ADME Predictions, and Anticancer Activities

Abstract

A new Cu (II) complex with 1,3-dimethyl-5-acetyl-barbituric acid was synthesized and characterized using elemental analysis, magnetic moment measurements, FTIR, and X-ray diffraction. Structural analysis revealed that the Cu (II) complex belongs to the triclinic system with the P -1 space group. The copper (II) ion is penta-coordinated via five oxygen atoms in a slightly distorted square-pyramidal geometry. Hirshfeld surface analysis confirmed the role of H-atom contacts in establishing the crystal packing, with the most significant contributions arising from H … H (48.6%) and H … O/O … H (30.2%) interactions. Hydrogen bonding and van der Waals interactions were identified as the dominant forces in the crystal packing. DNA binding studies demonstrated moderate groove binding, with an intrinsic binding constant (K_b) of 1.00 × 10⁴ M⁻¹. Viscosity measurements further supported the groove-binding interaction. Additionally, fluorescence quenching experiments with bovine serum albumin (BSA) revealed a static quenching mechanism with a binding constant (K_bin) of 3.21 × 10⁴ M⁻¹ indicating stable complex formation. The in vitro cytotoxicity of the Cu (II) complex revealed IC₅₀ values of 5.67 ± 0.07 μM for MDA-MB-231, 9.56 ± 0.24 μM for Caco-2, and 37.92 ± 0.03 μM for LNCaP cells after 72 h, with reduced toxicity toward noncancerous HEK-293 cells (IC₅₀ = 41.36 μM). The high selectivity index (SI = 8.13) for MDA-MB-231 highlights its strong selectivity compared to cisplatin. In silico ADME (absorption, distribution, metabolism, and excretion) predictions suggested favorable pharmacokinetic properties, including moderate solubility and low potential for drug–drug interactions, supporting the complex's potential as a therapeutic agent.