Design, synthesis, antibacterial evaluation, molecular docking, ADMET prediction, and DFT study of novel pyrido[2,3-b]pyrazine-based imine derivatives

Abstract

A series of novel pyrido[2,3-b]pyrazine-based imine derivatives (2a–2c) were synthesized by condensation of 7-bromopyrido[2,3-b]pyrazine-2,3(1H,4H)-dione with aliphatic primary amines and characterized using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HRMS). The antibacterial activity of the synthesized compounds was evaluated against selected bacterial strains using disc diffusion and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. The results demonstrated that all compounds exhibit antibacterial activity, with compound 2b showing the highest efficacy. Molecular docking studies targeting the ATP-binding domain of DNA gyrase B revealed favorable binding interactions, supporting a potential mechanism of action based on enzyme inhibition. In addition, in silico drug-likeness and ADMET predictions indicated that the compounds possess suitable pharmacokinetic properties, including high intestinal absorption, compliance with Lipinski’s rule of five, and low predicted toxicity. Density Functional Theory (DFT) calculations further revealed that all compounds share similar electronic properties, with moderate HOMO–LUMO energy gaps and balanced reactivity. Overall, the results highlight the potential of pyrido[2,3-b]pyrazine-based imine derivatives as promising antibacterial agents. Among them, compound 2b emerges as a lead candidate due to its optimal balance between biological activity, binding affinity, and pharmacokinetic properties.