Antibiotics | Hybrid 2-Quinolone–1,2,3-triazole Compounds Exhibit Potent Antibacterial Activity

This study successfully synthesized and evaluated novel quinolone-triazole hybrid molecules through rational design and computer-aided optimization. These compounds demonstrate significant inhibitory effects against both Gram-positive and Gram-negative bacterial strains, with minimum inhibitory concentrations (MIC) as low as 0.019 mg/mL, offering potential candidates for developing next-generation antibiotics.

 

Literature Overview
The article Hybrid 2-Quinolone–1,2,3-triazole Compounds: Rational Design, In Silico Optimization, Synthesis, Characterization, and Antibacterial Evaluation, published in Antibiotics, reviews the antibacterial potential of hybrid molecules based on quinolone and triazole scaffolds. The research team guided the synthesis of 29 candidate molecules through QSAR modeling, molecular docking, and molecular dynamics simulations, ultimately screening three compounds (4a–4c) with the highest activity and evaluating their antibacterial effects and pharmacokinetic properties.

Background Knowledge
Antimicrobial resistance has become a major global health challenge, necessitating the development of novel antibiotics. Quinolone compounds are widely studied for their broad-spectrum antibacterial activity and favorable pharmacokinetic properties, while 1,2,3-triazole structures exhibit strong bioactivity and molecular stability, making them common in drug design. This study combines both scaffolds using click chemistry to synthesize stable hybrid molecules, aiming to enhance antibacterial activity and reduce resistance risks. Computational design optimized molecular structures for improved receptor binding, which was experimentally validated. Although existing quinolone antibiotics show efficacy, resistance and side effects limit their application. This research provides a novel molecular design strategy for next-generation antimicrobial development.

 

 

Research Methods and Experiments
The team designed and screened 29 quinolone-triazole hybrid molecules using QSAR modeling and molecular docking. Three candidates (4a–4c) were synthesized and characterized via NMR, mass spectrometry, FT-IR, and UV-Vis spectroscopy. Antibacterial activity was evaluated through modified LasR-OC12 HSL receptor docking and in vitro diffusion assays for MIC determination. ADMET properties were predicted to assess oral bioavailability and metabolic stability.

Key Conclusions and Perspectives

• Quinolone-triazole hybrid molecules (4a–4c) exhibit significant antibacterial activity against Gram-positive (e.g., B. subtilis) and Gram-negative bacteria (e.g., E. coli), with 4a showing the lowest MIC of 19 µg/mL against B. subtilis
• Molecular docking reveals all synthesized compounds bind to the LasR-OC12 HSL receptor, with 4a achieving the lowest binding energy (−9.4 Kcal/mol), indicating stronger receptor affinity
• Molecular dynamics simulations show stable RMSD values for 4a–4c, suggesting minimal structural changes during receptor binding and good binding stability
• ADMET predictions confirm >95% intestinal absorption for all compounds, though 4a and 4b exhibit CYP3A4 inhibition potential, requiring further optimization for metabolic stability
• While current compounds show lower activity than ciprofloxacin, their unique scaffold offers a promising approach for multi-target antibiotics with reduced resistance risks, particularly for drug-resistant strains

Research Significance and Prospects
This study introduces a novel molecular scaffold design strategy for antimicrobial development. Future work should focus on optimizing substituents on quinolone and triazole rings to enhance efficacy and reduce toxicity. In vivo validation of antibacterial effects and pharmacokinetics will facilitate advancing these candidates to preclinical stages.

 

 

Conclusion
The study successfully designed and synthesized quinolone-triazole hybrid molecules, validating their receptor binding and antibacterial activity through in vitro experiments and molecular simulations. Although current compounds are less potent than clinical antibiotics, their scaffold provides a foundation for novel antimicrobials, particularly targeting resistance mechanisms. Future research should prioritize structural modifications and in vivo pharmacodynamic evaluation to improve antibacterial activity and pharmacokinetic profiles.

 

Ayoub El-Mrabet, Abderrahim Diane, Rachid Haloui, Amal Haoudi, and Nada Kheira Sebbar. Hybrid 2-Quinolone–1,2,3-triazole Compounds: Rational Design, In Silico Optimization, Synthesis, Characterization, and Antibacterial Evaluation. Antibiotics.