Design, Synthesis, and Molecular Docking Analysis of 4‐Quinolone‐2‐Carboxylic Acid Derivatives as Antimicrobial Agents

Abstract

AbstractQuinolones represent a class of potent antibacterial agents that primarily function by inhibiting bacterial topoisomerases and DNA gyrase. A crucial feature of their structure is a carboxylic acid group at the C‐3 position, which facilitates interaction with the active sites of these enzymes. Since the mid‐20th century, the emergence and proliferation of antimicrobial resistance (AMR) have posed significant challenges in society, necessitating the development of novel therapeutic agents. In this context, a new series of quinolone derivatives has been designed and synthesized based on transtorine. All synthesized compounds were tested against both Gram‐positive and Gram‐negative bacteria, as well as three fungal strains. Among the new compounds, 5a, 5d, and 5f demonstrated superior activity against Gram‐negative bacteria, with 5a showing notable effectiveness against P. aeruginosa compared to ciprofloxacin and norfloxacin. However, none of the compounds exhibited activity against fungal strains. Molecular docking studies revealed that compound 5a inhibited five bacterial proteins, primarily targeting bacterial cell wall synthesis. Additionally, ADMET parameters indicated that the promising compounds are suitable for oral administration with limited penetration across the blood–brain barrier compared to existing standards. This research indicates a potential pathway for developing new quinolone‐based antibiotics in the fight against AMR.