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.
Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity
