There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20 µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5 µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity.

中文翻译：

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新型1,2-二芳基吡唑并烷-3-酮类化合物的合成及其作为广谱抗菌剂的评价。

持续需要开发具有非传统机制的新型抗菌剂，以对抗对临床环境中使用的大多数抗生素不断出现的耐药性。我们在室内文库筛选中确定了新型吡唑烷酮衍生物作为抗菌命中物，并合成了几种衍生物以提高药效并增加发现的命中化合物的极性。肟衍生物24对大肠杆菌TolC，枯草芽孢杆菌和金黄色葡萄球菌表现出有希望的抗菌活性，MIC值分别为4、10和20 µg / mL。发现新的先导化合物24对大肠杆菌MurA和MurB酶均显示出较弱的双重抑制活性，IC50值分别为88.1和79.5 µM，这可以部分解释其抗菌作用。与先前报道的在结构上相关的吡唑烷二酮的比较表明，在4位上的肟官能度增强了对MurA的活性并恢复了对MurB酶的活性。化合物24可作为进一步开发具有潜在广谱活性的新型安全抗生素的先导。