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p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies

[ Vol. 17 , Issue. 2 ]

Author(s):

İrem Bozbey, Suat Sari, Emine Şalva, Didem Kart and Arzu Karakurt*   Pages 169 - 183 ( 15 )

Abstract:


Background: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immunecompromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells.

Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions.

Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling.

Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 µM. In this line, 3 was the most potent with an IC50 value of 82.18 μM followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH.

Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.

Keywords:

Antimicrobial activity, azoles, CYP51, cytotoxic effects, molecular modeling, oxime ester.

Affiliation:

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Inonu University, 44280, Malatya, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Inonu University, 44280, Malatya, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Inonu University, 44280, Malatya

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