Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
Bioorg Chem. 2020 Jun;99:103759. doi: 10.1016/j.bioorg.2020.103759. Epub 2020 Mar 14.
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 IC 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.
不断需要开发具有非传统机制的新型抗菌剂，以对抗临床应用中大多数抗生素不断出现的耐药性。我们在内部文库筛选中发现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，以提高发现命中物的效力和增加其极性。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。新的先导化合物 24 被发现对大肠杆菌 MurA 和 MurB 酶具有较弱的双重抑制活性，IC 值分别为 88.1 和 79.5 µM，这可以部分解释其抗菌作用。与先前报道的结构相关的吡唑烷二酮的比较表明，4 位的肟官能团增强了对 MurA 的活性并恢复了对 MurB 酶的活性。化合物 24 可以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化合物。
