Synthesis of Antimicrobial Quinoline Derivatives Enabled by Synergistic Pd/Enamine Catalysis: Experimental and Computational Study

Abstract

An intermolecular addition of acetophenone derivatives to unactivated alkenes was developed through Pd-(II)/amine cooperative catalysis. This dual catalytic system functions by activating the amide-containing alkene via Pd-(II) coordination while simultaneously enhancing the nucleophilicity of the α-carbon of acetophenones through enamine catalysis, thereby facilitating the C-C bond-forming reaction. Five quinoline-based amide derivatives were designed and synthesized to explore their potential as biologically active agents. The synthesized compounds were structurally characterized using the standard NMR technique and subsequently evaluated for their antimicrobial activity against a panel of pathogenic bacterial and fungal strains. The five derivatives exhibited significant inhibitory effects, with minimum inhibitory concentrations (MICs) comparable to or better than those of reference drugs. To gain insight into the molecular basis of their biological activity, molecular docking studies were performed against relevant microbial target enzymes, revealing favorable binding interactions and high docking scores. Furthermore, molecular dynamics (MD) simulations were carried out to assess the stability and conformational behavior of the most active ligand-protein complexes over time, supporting their potential as stable bioactive candidates. In addition, ADMET in silico predictions indicated good drug-likeness, acceptable pharmacokinetic profiles, and low toxicity risk, reinforcing their potential as promising scaffolds for antimicrobial drug development.