New azole antifungal agents with novel modes of action: synthesis and biological studies of new tridentate ligands based on pyrazole and triazole
| Autor: | Rachid Touzani, Corey Nislow, Mohammed Bellaoui, Charles Boone, H. Bendaha, Guri Giaever, Rachid Souane, Sghir El Kadiri, Lisa Yu, Grant W. Brown |
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| Rok vydání: | 2011 |
| Předmět: |
Antifungal Agents
Magnetic Resonance Spectroscopy Tertiary amine DNA Repair Spectrophotometry Infrared DNA damage Saccharomyces cerevisiae Triazole Pyrazole Ligands 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Drug Discovery Protein Kinase C 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology 010405 organic chemistry Chemistry Organic Chemistry Cell Cycle Biological activity General Medicine Triazoles biology.organism_classification Yeast 0104 chemical sciences 3. Good health Biochemistry Azole Pyrazoles |
| Zdroj: | European journal of medicinal chemistry. 46(9) |
| ISSN: | 1768-3254 |
| Popis: | The synthesis and extensive biological study of two new tridentates ligands based on pyrazole and triazole are described. The antifungal activity against the budding yeast cells of the newly synthesized compounds was determined. These compounds were toxic to yeast cells. Cell cycle analysis suggested that treatment with these compounds impairs cell division in G1 of the cell cycle. Using yeast-based functional genomics technologies, we found that these compounds tolerance requires DNA repair pathway and SKI complex function. We have also found that the PKC1 heterozygous deletion strain was the most sensitive to these compounds using HaploInsufficiency Profiling, suggesting that the Pkc1 protein may be the target for these compounds. These results strongly suggest that these compounds induce DNA damage and thus exert a different mechanism of action compared to other azole derivatives. These two compounds might therefore represent promising lead compounds for further development of antifungal drugs for human therapy. |
| Databáze: | OpenAIRE |
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