title: New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies.
abstract: Azole antifungals are potent inhibitors of fungal lanosterol 14α demethylase (CYP51) and have been used for eradication of systemic candidiasis clinically. Herein we report the design, synthesis, and biological evaluation of a series of 1-phenyl/1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol esters. Many of these derivatives showed fungal growth inhibition at very low concentrations. Minimal inhibition concentration (MIC) value of 15 was 0.125 μg/mL against Candida albicans. Additionally, some of our compounds, such as 19 (MIC: 0.25 μg/mL), were potent against resistant C. glabrata, a fungal strain less susceptible to some first-line antifungal drugs. We confirmed their antifungal efficacy by antibiofilm test and their safety against human monocytes by cytotoxicity assay. To rationalize their mechanism of action, we performed computational analysis utilizing molecular docking and dynamics simulations on the C. albicans and C. glabrata CYP51 (CACYP51 and CGCYP51) homology models we built. Leu130 and T131 emerged as possible key residues for inhibition of CGCYP51 by 19.
authors.affiliation: Department of Pharmaceutical Chemistry, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey.
authors.forename: İnci Selin
authors.initials: İS
authors.lastname: Doğan
authors.affiliation: Department of Pharmaceutical Chemistry, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey. Electronic address: sesarac@hacettepe.edu.tr.
authors.forename: Selma
authors.initials: S
authors.lastname: Saraç
authors.affiliation: Department of Pharmaceutical Chemistry, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey.
authors.forename: Suat
authors.initials: S
authors.lastname: Sari
authors.affiliation: Department of Pharmaceutical Microbiology, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey.
authors.forename: Didem
authors.initials: D
authors.lastname: Kart
authors.affiliation: Department of Bioinformatics and Genetics, Kadir Has University, Faculty of Engineering and Natural Sciences, 34083, Istanbul, Turkey.
authors.forename: Şebnem
authors.initials: Ş
authors.lastname: Eşsiz Gökhan
authors.affiliation: Department of Pharmaceutical Technology, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey.
authors.forename: İmran
authors.initials: İ
authors.lastname: Vural
authors.affiliation: Department of Pharmaceutical Chemistry, Hacettepe University, Faculty of Pharmacy, 06100, Ankara, Turkey.
authors.forename: Sevim
authors.initials: S
authors.lastname: Dalkara
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D005656:Fungal Proteins / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009000:Monocytes / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D000935:Antifungal Agents; D001393:Azoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D005656:Fungal Proteins; D003577:Cytochrome P-450 Enzyme System
keywords: Antifungal; Azoles; CYP51; Candida species; Molecular docking; Molecular dynamics simulation