Skibinska Monika, Warowicka Alicja, Crousse Benoît, Cytlak Tomasz
Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.
BioCIS UMR 8076 CNRS, Building Henri Moissan, Université Paris-Saclay, avenue des sciences, 91400 Orsay, France.
ACS Omega. 2025 Apr 28;10(17):18062-18072. doi: 10.1021/acsomega.5c01562. eCollection 2025 May 6.
A new series of C-3 phosphonated 4-CF--lactams was stereoselectively synthesized from corresponding 4-CF--lactams, applying two different protocols for phosphonate group incorporation. The first method involved the direct incorporation of a phosphonate (V) moiety at the C-3 position although it was limited by steric hindrance. The second approach enabled the incorporation of a less bulky phosphonite (III), which was subsequently oxidized to the corresponding phosphonate (V). The synthesized -lactam ring features both fluorinated and phosphonate substituents, which are known for their biological significance, such as enhancing membrane permeability, improving binding interactions, and inhibiting enzymes. Considering these properties, along with the inherent antibacterial potential of -lactams, we evaluated the antibacterial activity of selected C-3 phosphonated 4-CF--lactams against four bacterial strains ( (), methicillin-resistant (MRSA), , ()). Applying the disk diffusion method, MIC measurements, and -lactamase inhibition assays, compounds and emerged as the most promising candidates in this preliminary antibacterial evaluation.
通过应用两种不同的膦酸酯基团引入方案，从相应的4-三氟甲基内酰胺立体选择性地合成了一系列新的C-3膦酸化4-三氟甲基内酰胺。第一种方法涉及在C-3位直接引入膦酸酯（V）部分，尽管它受到空间位阻的限制。第二种方法能够引入体积较小的亚膦酸酯（III），随后将其氧化为相应的膦酸酯（V）。合成的内酰胺环同时具有氟化和膦酸酯取代基，这些取代基因其生物学意义而闻名，例如增强膜通透性、改善结合相互作用和抑制酶。考虑到这些特性以及内酰胺固有的抗菌潜力，我们评估了所选C-3膦酸化4-三氟甲基内酰胺对四种细菌菌株（大肠杆菌（Escherichia coli）、耐甲氧西林金黄色葡萄球菌（MRSA）、肺炎克雷伯菌（Klebsiella pneumoniae）、铜绿假单胞菌（Pseudomonas aeruginosa））的抗菌活性。通过纸片扩散法、最低抑菌浓度（MIC）测量和β-内酰胺酶抑制试验，化合物4和6在这项初步抗菌评估中成为最有前景的候选物。
