title: New azole antifungal agents with novel modes of action: synthesis and biological studies of new tridentate ligands based on pyrazole and triazole.
abstract: 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.
authors: Laboratoire de Chimie Appliquée et Environnement, Département de Chimie, Faculté des Sciences, Université Mohamed Premier, BP 524, 60000 Oujda, Morocco.
authors: Hasnae
authors: H
authors: Bendaha
authors: Lisa
authors: L
authors: Yu
authors: Rachid
authors: R
authors: Touzani
authors: Rachid
authors: R
authors: Souane
authors: Guri
authors: G
authors: Giaever
authors: Corey
authors: C
authors: Nislow
authors: Charles
authors: C
authors: Boone
authors: Sghir
authors: S
authors: El Kadiri
authors: Grant W
authors: GW
authors: Brown
authors: Mohammed
authors: M
authors: Bellaoui
mesh_terms: D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle; D004260:DNA Repair; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D013055:Spectrophotometry, Infrared; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D008024:Ligands; D011720:Pyrazoles; D014230:Triazoles; D011493:Protein Kinase C