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Phenothiazinium-fluoroquinolone drug conjugates.
Mark Wainwright1, Ami Shah, Katie Meegan
1School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. mark_wainwright@hotmail.com
International Journal of Antimicrobial Agents
|January 12, 2010
Summary
New norfloxacin conjugates show enhanced antibacterial activity against Staphylococcus aureus and Escherichia coli compared to methylene blue. While lacking photodynamic properties, these conjugates exhibit stronger DNA binding, suggesting alternative mechanisms for their antimicrobial effects.
Area of Science:
- Medicinal Chemistry
- Photodynamic Therapy
- Antimicrobial Agents
Background:
- Methylene blue derivatives are known photosensitizers with antimicrobial properties.
- Norfloxacin is a fluoroquinolone antibiotic with DNA gyrase inhibitory activity.
- Combining these scaffolds may lead to novel antimicrobial agents with improved efficacy.
Purpose of the Study:
- To synthesize and evaluate a series of 3-dialkylaminophenothiazinium-7-norfloxacin conjugates for antibacterial activity.
- To compare the photophysical properties and photoantibacterial action of these conjugates with methylene blue derivatives.
- To investigate the DNA binding capabilities of the synthesized conjugates.
Main Methods:
- Synthesis of homologous series of 3-dialkylaminophenothiazinium-7-norfloxacin conjugates.
- Synthesis of corresponding symmetrical methylene blue derivatives.
- Antibacterial screening against Staphylococcus aureus and Escherichia coli.
- Photophysical property assessment including singlet oxygen generation.
- DNA binding studies using intercalation assays.
Main Results:
- Norfloxacin conjugates retained methylene blue's photoproperties but did not generate significant singlet oxygen.
- Photoantibacterial action was not significantly enhanced compared to methylene blue homologues.
- Both conjugates and homologues showed greater activity than methylene blue against S. aureus and E. coli.
- Norfloxacin conjugates demonstrated significantly higher DNA binding via intercalation than methylene blue homologues.
Conclusions:
- The synthesized norfloxacin conjugates exhibit potent antibacterial activity against Gram-positive and Gram-negative bacteria, potentially through mechanisms beyond photodynamic action.
- Enhanced DNA intercalation suggests a significant role for DNA binding in the observed antimicrobial efficacy of these novel conjugates.
- Further research into the non-photodynamic mechanisms of action is warranted for these promising antibacterial agents.
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