Abstract
Various 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles (11–20) were prepared by the reaction of aryl substituted hydrazones of 4-fluorobenzoic acid hydrazide (1–10) with acetic anhydride. The structures of the synthesized compounds 11–20, were confirmed by UV, IR, 1H-NMR and mass spectroscopic methods. Antifungal evaluation of the hydrazide–hydrazones 1–10 and corresponding 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles 11–20, against clinical and standard Candida pathogens have been performed by using agar diffusion to indentify the active compounds, which were later subjected to a broth microdilution assay to justify the activity level in terms of minimum inhibitory concentrations (MIC). 4-Fluorobenzoic acid [(5-bromothiophen-2-yl)methylene]hydrazide, showed the highest inhibitory activity against Candida albicans (MIC: 125 μg/ml), and when compared with ketoconazole. In addition, bioauthographic antifungal activity against plant pathogenic fungi such as Colletotrichum, Botrytis, Fusarium, and Phomopsis was conducted. 4-Fluorobenzoic acid [(5-bromothiophen-2-yl)methylene]hydrazide was the most active analog against P. viticola with 91% inhibition at 30 μM after 144 h. Furthermore, known and the newly synthesized compounds were also screened through a panel of bioassays to determine their anti-inflammatory, cytotoxic, and antioxidant activities in mammalian cells. 3-Acetyl-5-(4-fluorophenyl)-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole, showed a strong inhibition of NF-κB-dependent transcription in SW1353 cells with IC50 value of 0.75 μg/ml. 4-Fluorobenzoic acid [(3-hydroxy-4-methoxyphenyl)methylene]hydrazide, and 3-acetyl-5-(4-fluorophenyl)-2-(3-hydroxy-4-methoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole on intracellular ROS generation in PMA induced HL-60 cells demonstrated potent activity with IC50 values of 0.9 μg/ml. A strong inhibition of the activity of iNOS activity in LPS induced RAW 264.7 cells was observed for 3-acetyl-5-(4-fluorophenyl)-2-(4-hydroxyphenyl)-2,3-dihydro-1,3,4-oxadiazole with IC50 value of 0.3 μg/ml.
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Acknowledgments
This project was financially supported by the Marmara University Research Center (Project number SAG-060-210). The authors express their gratitude for USDA, ARS, NPURU financial support. Also Ms. J. Linda Robertson, Ms. Ramona Pace, and Ms. Xiaoning Wang for assistance with the antifungal assay, Mr. John Trott, Mr. Paul Bates, and Ms. Katherine Martin for bioassays for anti-inflammatory, antioxidant, and cytotoxic activities are acknowledged.
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Koçyiğit-Kaymakçıoğlu, B., Oruç-Emre, E.E., Ünsalan, S. et al. Synthesis and biological activity of hydrazide–hydrazones and their corresponding 3-acetyl-2,5-disubstituted-2,3-dihydro-1,3,4-oxadiazoles. Med Chem Res 21, 3499–3508 (2012). https://doi.org/10.1007/s00044-011-9882-z
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DOI: https://doi.org/10.1007/s00044-011-9882-z