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

• Published in: ChemistrySelect (Weinheim) Vol. 9; no. 44
• Main Authors: Verma, Ekta, Mishra, Shweta, Pal, Mahendra Kumar, Patil, Shailendra, Gajbhiye, Asmita
• Format: Journal Article
• Language: English
• Published: 25-11-2024
• Subjects: ADMET; Antibacterial; Antifungal; Molecular docking; Quinolones
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202403704

Quinolones 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.
The novel 4‐quinolone‐2‐carboxylic acid derivatives are synthesized and characterized, demonstrating significant antibacterial activity against Gram‐negative bacteria, particularly P. aeruginosa and E. coli. The compound 2‐(1‐(4‐chlorobenzyl)‐4‐oxo‐1,4‐dihydroquinolin‐2‐yl)acetic acid (5a) shows strong binding energy in molecular docking studies against LpxC and PBP3 enzymes, suggesting effective mechanisms of action. Additionally, the derivatives indicate favorable for ADMET profiles, supporting their potential for oral formulations with reduced toxicity.