Synthesis and antimicrobial testing of 5-fluorouracil derivatives

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Antibiotic resistance necessitates novel therapeutic strategies against multidrug-resistant microorganisms.
• 5-fluorouracil (5-FU) exhibits intrinsic antibacterial properties but faces limitations due to toxicity.
• Developing effective 5-FU derivatives is crucial for combating resistant bacterial infections.

Purpose of the Study:

• To synthesize and evaluate novel 5-FU derivatives for antibacterial efficacy against pathogenic bacteria.
• To investigate the mechanism of action of potent 5-FU derivatives.
• To assess the therapeutic potential of these derivatives against multidrug-resistant strains.

Main Methods:

• Synthesis of tri-hexylphosphonium substituted 5-FU derivatives.
• Determination of antibacterial susceptibility, including minimal inhibitory concentration (MIC).
• Electron microscopy, membrane permeabilization, and depolarization assays.
• Assessment of bacterial motility and hemolytic activity.

Main Results:

• Tri-hexylphosphonium substituted 5-FU derivatives (6a, 6b, 6c) demonstrated significant activity against Gram-positive and Gram-negative bacteria.
• Compound 6c, with an asymmetric linker, exhibited superior antibacterial efficacy.
• Electron microscopy revealed cell wall and cytosolic damage in Staphylococcus aureus and plasmolysis in Escherichia coli.
• Compound 6c consistently inhibited bacterial growth across resistant profiles, inducing membrane alterations and reducing motility.
• Compound 6c displayed non-hemolytic activity.

Conclusions:

• Novel phosphonium-based 5-FU derivatives possess potent antibacterial activity.
• Compound 6c is a promising candidate for treating multidrug-resistant bacterial infections due to its efficacy, mechanism of action, and safety profile.
• Further research into 5-FU derivatives could lead to new treatments for challenging bacterial infections.