Department of Chemistry and Centre for Environmental Sciences and Engineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.
Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow-226031, India.
Dalton Trans. 2023 Feb 14;52(7):1876-1884. doi: 10.1039/d2dt03365h.
Three platinum(II)-N-heterocyclic carbene (NHC) compounds Pt(L)Cl (1), Pt(L)(COD) (2) and [Pt(L)Cl] (3) were synthesized bearing pyridyl-functionalized butenyl-tethered (LH) and -butyl tethered (LH) NHC ligands, and their antibacterial activity against clinically relevant human pathogens was evaluated. Complex 1 was designed to have one of its metal coordination sites masked with a hemilabile butenyl group. The antibacterial activity spectrum against the ESKAPE panel of pathogens shows superior activity of 1 compared to 2 and 3 against the Gram-positive pathogen. Complex 1 showed equipotent activity against clinical drug-resistant and isolates. Furthermore, 1 demonstrated concentration-dependent bactericidal activity with a long post-antibiotic effect, eradicated preformed biofilm and synergized with gentamicin and minocycline for combinatorial antimicrobial therapy. Under conditions, 1 displayed potent activity in reducing bacterial load in a murine thigh infection model, similar to vancomycin, albeit at 2.5× less dosage. An array of experiments reveals key characteristics for the hemilabile complex 1 as a potential anti-staphylococcal drug.
三种铂(II)-N-杂环卡宾（NHC）化合物Pt(L)Cl（1）、Pt(L)(COD)（2）和[Pt(L)Cl]（3）被合成出来，它们带有吡啶基功能化的丁烯基键合（LH）和-丁基键合（LH）NHC 配体，并评估了它们对临床相关人类病原体的抗菌活性。配合物 1 的设计是为了使其中一个金属配位位点被一个半惰性的丁烯基基团屏蔽。对 ESKAPE 病原体面板的抗菌活性谱显示，1 比 2 和 3 对革兰氏阳性病原体具有更高的活性。配合物 1 对临床耐药的 和 分离株表现出等效的活性。此外，1 表现出浓度依赖性杀菌活性，具有较长的抗生素后效应，根除已形成的生物膜，并与庆大霉素和米诺环素协同作用，用于组合抗菌治疗。在体内条件下，1 在减少小鼠大腿感染模型中的细菌负荷方面表现出强大的活性，与万古霉素相似，尽管剂量低 2.5 倍。一系列实验揭示了半惰性配合物 1 作为一种潜在抗葡萄球菌药物的关键特征。
