Amide-functionalized cholic acid hybrids: design, bioactivity, and computational analysis

Abstract

A series of amide-linked cholic acid derivatives (3a–f) was synthesized through an efficient one-pot acyl chloride coupling strategy, yielding structurally diverse hybrids under mild conditions. The antioxidant potential of these derivatives was evaluated using the DPPH radical scavenging assay, with compounds 3b–d exhibiting the most pronounced activity, in an average of 50%. Antibacterial efficacy was investigated against both Staphylococcus aureus and Escherichia coli, revealing preferential activity toward Gram-positive strains, particularly for aromatic amide-bearing analogs. To elucidate the underlying molecular interactions, in silico investigations, including molecular docking, molecular dynamics simulations, and MM-PBSA binding free energy calculations, were conducted against the ATP-binding domain of bacterial DNA gyrase (GyrB). These computational studies revealed stable binding modes and favorable energetics that correlate with observed bioactivity. Density functional theory and ADMET predictions further supported the drug-like profiles and chemical reactivity of the most active compounds. These results demonstrate that the cholic acid scaffold can be effectively tailored to yield multifunctional agents with antioxidant and selective antibacterial properties, providing a promising framework for the development of novel antimicrobial candidates.