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New 1,5 and 2,5-disubstituted tetrazoles-dependent activity towards surface barrier of Candida albicans
- Source :
- European journal of medicinal chemistry. 145
- Publication Year :
- 2017
-
Abstract
- A series of novel tetrazole derivatives was synthetized using N-alkylation or Michael-type addition reactions, and screened for their fungistatic potential against Candida albicans (the lack of endpoint = 100%). Among them, the selected compounds 2d, 4b, and 6a differing in substituents at the tetrazole ring were non-toxic to Galleria mellonella larvae in vivo and exerted slight toxicity against Caco-2 in vitro (CC50 at 256 μg/mL). An antagonistic effect of tetrazole derivatives 2d, 4b, and 6a respectively in combination with Fluconazole was shown using the checker board and colorimetric methods (fractional inhibitory concentration indexes FICIs >1). The most active 2d and 6a displayed an inverse relation between MICs in the presence of exogenous ergosterol, the effect was opposite to Itraconazole and Amphotericin B. The differences between 6a's and 2d's action mode were noted. Combining both flow cytometry and fluorescence image analyses respectively showed the complexity of planktonic and biofilm cell demise mode under the tetrazole derivatives tested. The following evidences for 6a's interaction with fungal membrane were noted: necrosis-like programmed cell death (97.03 ± 0.88), DNA denaturation (no laddering), mitochondrial damage (XTT assay), reduced adhesion to human epithelium (>50% at 0.0313 μg/mL, p ≤ .05), irregular deposit of chitin, and attenuated morphogenesis in mature biofilm. The treatment with 6a reduced pathogenicity of C. albicans during infection in G. mellonella. Contrariwise, 2d enhancing fungal adhesion displayed mechanism targeted to the cell wall (due to the presence of 3-chloropropyl clubbed with aryltetrazole) in the presence of osmotic protector. Under 2d, the accidental cell death (88.60% ± 4.81) was observed. In conclusion, all tetrazole derivatives were obtained in satisfactory yields (60–95%) using efficient, simple and not expensive methods. Fungistatic and slightly anticancer tetrazole derivatives with the novel action mode can circumvent an appearance of antifungal-resistant strains. These results indicate that they are worthy of further studies.
- Subjects :
- 0301 basic medicine
Programmed cell death
Antifungal Agents
Cell Survival
030106 microbiology
Tetrazoles
Microbial Sensitivity Tests
Flow cytometry
Cell wall
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Chitin
Drug Discovery
Candida albicans
medicine
Humans
Tetrazole
Pharmacology
Ergosterol
medicine.diagnostic_test
biology
Dose-Response Relationship, Drug
Molecular Structure
Organic Chemistry
Biofilm
General Medicine
biology.organism_classification
chemistry
Biochemistry
Caco-2 Cells
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 145
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....319071ba435f638907cd9680b1d8a360