Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, China.
Bioorg Chem. 2020 Dec;105:104398. doi: 10.1016/j.bioorg.2020.104398. Epub 2020 Oct 21.
A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213 ,144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22-[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro antibacterial effect against MRSA (MIC = 1 μg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo antibacterial activities of compound 59 against MRSA were further evaluated employing thigh infection model. And compound 59 (-8.89 log CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 enzymes. The PK properties of compound 59 were then measured. The half-life (t), clearance rate (Cl) and the area under the plasma concentration time curve (AUC) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 μg·h/mL, respectively.
在温和条件下，通过点击反应，合成了一系列新型截短侧耳素衍生物，这些衍生物在 C14 侧链上含有哌嗪环、1,2,3-三唑和仲胺。采用肉汤稀释法评价了合成衍生物对 4 株金黄色葡萄球菌（MRSA ATCC 43300、ATCC 29213、144 和 AD3）和 1 株大肠杆菌（ATCC 25922）的体外抗菌活性。在这些衍生物中，22-[2-（4-（（4-硝基苯哌嗪）甲基）-1,2,3-三唑-1-基）-1-（哌嗪-1-基）乙基-1-酮]脱氧截短侧耳素（化合物 59）对 MRSA 的体外抗菌效果最为显著（MIC=1μg/mL）。此外，化合物 59 的杀菌动力学比泰妙菌素快，对 MRSA 的 PAE 比泰妙菌素长。此外，采用大腿感染模型进一步评价了化合物 59 对 MRSA 的体内抗菌活性。化合物 59（-8.89 log CFU/mL）的活性优于泰妙菌素。进一步对化合物 59 进行 CYP450 抑制试验，结果表明其对 CYP1A2、CYP2E1、CYP2D6 和 CYP3A4 酶有低到中度抑制作用。然后测定了化合物 59 的 PK 性质。化合物 59 的半衰期（t）、清除率（Cl）和血浆浓度时间曲线下面积（AUC）分别为 0.74 h、0.29 L/h/kg 和 46.28μg·h/mL。
