Details

Autor(en) / Beteiligte

• Doğan, İnci Selin
• Saraç, Selma
• Sari, Suat
• Kart, Didem
• Eşsiz Gökhan, Şebnem
• Vural, İmran
• Dalkara, Sevim

Titel

New azole derivatives showing antimicrobial effects and their mechanism of antifungal activity by molecular modeling studies

Ist Teil von

• European journal of medicinal chemistry, 2017-04, Vol.130, p.124-138

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •A set of new ester derivatives were designed and synthesized by modifying the general structure of azole antifungals.•Most of the compounds possessed good activity against Candida species without cytotoxicity on human monocytic cells.•Compound 19 and 28 were found highly potent against clinically resistant Candida glabrata strain.•Homology models of CACYP51 and CGCYP51 were constructed to rationalize mechanism of action of the compounds.•L130 and T131 were predicted through molecular modelling studies as key residues for CGCYP51 inhibition.