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Modulation of key antioxidant enzymes and cell cycle arrest as a possible antifungal mode of action of cinnamaldehyde based azole derivative
Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2022-08-04 , DOI: 10.1016/j.bmcl.2022.128922
Mohmmad Younus Wani 1 , Aijaz Ahmad 2 , Faisal Mohammed Aqlan 1 , Abdullah Saad Al-Bogami 1
Affiliation  

Although Candida auris was only identified in the year 2009, it has rapidly spread in more than a dozen countries and is proving more deadly and notorious. In our previous studies, we reported on the tremendous antifungal potential of a series of cinnamaldehyde based azole derivatives against fluconazole susceptible and resistant clinical isolates of Candida albicans and identified a promising lead molecule (6f). In this study, the effect of this compound on the viability and physiology of cell death in C. auris was assessed. The impact of compound 6f on cell cycle, oxidative stress enzymes and transcriptional profile of genes encoding these oxidative stress enzymes was also analysed. The results confirmed that compound 6f possessed the minimum inhibitory concentration of 0.98 µg/mL and prevented the growth and caused death in yeast cells. Furthermore, the compound at subinhibitory and inhibitory concentrations blocked the cell cycle in C. auris at S phase and G2/M phase and inhibited expression as well as activity of antioxidant enzymes that resulted in production of reactive oxygen species. Altogether, compound 6f showed potential antifungal activity against a virulent strain of C. auris and was able to induce oxidative stress and arrested cell cycle in C. auris and therefore, it can be considered as a strong candidate for antifungal drug development against C. auris.



中文翻译:

调节关键抗氧化酶和细胞周期阻滞作为肉桂醛唑衍生物可能的抗真菌作用方式

尽管Candida a uris 是在 2009 年才被发现的,但它已在十几个国家迅速传播,并且被证明更加致命和臭名昭著。在我们之前的研究中,我们报道了一系列基于肉桂醛的唑类衍生物对氟康唑敏感和耐药的白色念珠菌临床分离株的巨大抗真菌潜力,并确定了一种有前景的先导分子 (6f)。在这项研究中,该化合物对C. auris中细胞死亡的活力和生理学的影响进行了评估。还分析了化合物6f对细胞周期、氧化应激酶和编码这些氧化应激酶的基因转录谱的影响。结果证实,化合物6f的最低抑菌浓度为0.98 µg/mL,可抑制酵母细胞的生长并导致其死亡。此外,亚抑制和抑制浓度的化合物在 S 期和 G2/M 期阻断了念珠菌中的细胞周期,并抑制了导致活性氧产生的抗氧化酶的表达和活性。总之,化合物 6f 对C.auris的毒性菌株显示出潜在的抗真菌活性,并且能够在C.auris中诱导氧化应激并阻止细胞周期因此,它可以被认为是针对C. auris的抗真菌药物开发的有力候选者。

更新日期:2022-08-05
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