Bis-guanylhydrazones as efficient anti-Candida compounds through DNA interaction
Jelena Lazić1,2, Vladimir Ajdačić1, Sandra Vojnovic2
1Faculty of Chemistry, University of Belgrade, Studentski trg 16, P.O. Box 51, Belgrade, 11158, Serbia.
Applied Microbiology and Biotechnology
|January 14, 2018
Summary
Novel bis-guanylhydrazone derivatives show potent antifungal activity against Candida species. Compound BG3 targets fungal DNA and induces apoptosis, demonstrating potential as a new antifungal agent with low cytotoxicity.
Area of Science:
- Mycology
- Medicinal Chemistry
- Biochemistry
Background:
- Candida species are significant causes of opportunistic mycoses, necessitating new antifungal drugs.
- Hydrazone and guanidine compounds exhibit promising antifungal properties.
- Bis-guanylhydrazone derivatives offer a novel structural class for antifungal development.
Purpose of the Study:
- To synthesize and evaluate novel bis-guanylhydrazone derivatives for antifungal activity.
- To investigate the mechanism of action of these compounds, particularly their interaction with fungal DNA.
- To assess the potential of BG3 as a therapeutic antifungal agent.
Main Methods:
- Synthesis of four bis-guanylhydrazone derivatives (BG1-4).
- Determination of minimal inhibitory concentrations (MICs) against Candida species and biofilms.
- In vitro DNA interaction studies (circular dichroism, molecular docking, DNA-binding competition).
- Apoptosis induction assays, reactive oxygen species (ROS) measurement, mitochondrial membrane potential assessment.
- Synergy testing with amphotericin B, cytotoxicity assays, and inhibition of Candida invasion.
Main Results:
- Bis-guanylhydrazones exhibited MICs between 2 and 15.6 μg/mL against Candida species and were effective against biofilms.
- Compounds demonstrated significant DNA-binding capabilities.
- BG3 induced apoptosis in Candida albicans via metacaspase activation and mitochondrial dysfunction, with limited ROS involvement.
- BG3 showed synergistic effects with amphotericin B.
- BG3 displayed low cytotoxicity and inhibited Candida invasion of epithelial cells.
Conclusions:
- Bis-guanylhydrazone derivatives are potent antifungal agents with a novel DNA-targeting mechanism.
- BG3 exhibits promising characteristics, including apoptosis induction and synergistic activity, for further development.
- BG3 represents a potential candidate for the antifungal drug pipeline, targeting DNA interactions.
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