New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies
- Resource Type
- Authors
- Selma Saraç; Şebnem Eşsiz Gökhan; Sevim Dalkara; Didem Kart; Suat Sari; Imran Vural; İnci Selin Doğan
- Source
- European Journal of Medicinal Chemistry. 130:124-138
- Subject
- Azoles
Models, Molecular
0301 basic medicine
Antifungal Agents
030106 microbiology
CYP51
Pharmacology
Antifungal
Monocytes
Microbiology
Fungal Proteins
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Anti-Infective Agents
Cytochrome P-450 Enzyme System
Molecular dynamics simulation
Drug Discovery
Candida species
medicine
Cytochrome P-450 Enzyme Inhibitors
Humans
Candida albicans
Cytotoxicity
Cells, Cultured
Candida
chemistry.chemical_classification
biology
Lanosterol
Organic Chemistry
General Medicine
biology.organism_classification
medicine.disease
Antimicrobial
Molecular Docking Simulation
030104 developmental biology
Mechanism of action
chemistry
Molecular docking
biology.protein
Azole
Demethylase
Systemic candidiasis
medicine.symptom
- Language
- ISSN
- 0223-5234
Azole antifungals are potent inhibitors of fungal lanosterol 14 alpha 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 mu g/mL against Candida albicans. Additionally some of our compounds such as 19 (MIC: 0.25 mu g/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. (C) 2017 Elsevier Masson SAS. All rights reserved.