Volume 8, Issue 18 e202300134
Research Article

Design, Synthesis, and Molecular Modeling of New and Safe Azole Oxime Esters with Promising Antifungal Activity

Sibel Yurtoğlu

Sibel Yurtoğlu

Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, Turkey

Turkish Medicines and Medical Devices Agency, Ministry of Health, Ankara, Turkey

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Assist. Prof. Suat Sari

Corresponding Author

Assist. Prof. Suat Sari

Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, Turkey

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Assist. Prof. Didem Kart

Assist. Prof. Didem Kart

Department of Pharmaceutical Microbiology, Hacettepe University, Ankara, Turkey

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Prof. Suna Sabuncuoğlu

Prof. Suna Sabuncuoğlu

Department of Pharmaceutical Toxicology, Hacettepe University, Ankara, Turkey

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Prof. Selma Saraç

Prof. Selma Saraç

Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, Turkey

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First published: 09 May 2023

Graphical Abstract

A series of 2-(1H-imidazol-1-yl-1-phenylethanone oxime esters were synthesized and tested for their antimicrobial effects. The sorbic acid ester was found to have promising ani-Candida activity, as well as minimal toxicity to healthy cells. Molecular modelling predicted strong interactions with the heme co-factor of lanosterol 14 α-demethylase, the fungal cytochrome p450 enzyme targeted by azoles.

Abstract

Fungal infections have become a major public health issue with dramatically increasing morbidity, mortality and cost of hospitalization. Azole antifungals are first-in-line medications against most types of mycoses and azoles having an oxime moiety, although not extensively investigated, were reported to have great antifungal potential, as well as, activity against Gram-positive bacteria. In the current study, a new series of 2-(1H-imidazol-1-yl)-1-phenylethanone oxime esters (5 al) were synthesized and tested for their antimicrobial activities. The sorbic acid ester (5 c) was found to be highly promising against Candida albicans and Candida parapsilosis (MIC=4 μg/ml). In addition, 5 c was not toxic to the healthy murine fibroblast. Molecular modelling suggested that the compounds were druglike, orally available, not substrates of efflux pumps, and probably acted through fungal CYP51 inhibition, which is the major action mechanism of azole antifungals.

Conflict of interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.