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; Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China.
Bioorg Med Chem. 2021 May 15;38:116138. doi: 10.1016/j.bmc.2021.116138. Epub 2021 Apr 2.
A series of novel pleuromutilin derivatives were designed and synthesized with 1,2,4-triazole as the linker connected to benzoyl chloride analogues under mild conditions. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, AD3 and 144) were tested by the broth dilution method. Most of the synthesized derivatives displayed potent activities, and 22-(3-amino-2-(4-methyl-benzoyl)-1,2,4-triazole-5-yl)-thioacetyl)-22-deoxypleuromutilin (compound 12) was found to be the most active antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the time-kill curves showed compound 12 had a certain inhibitory effect against MRSA in vitro. The in vivo antibacterial activity of compound 12 was further evaluated using MRSA infected murine thigh model. Compound 12 exhibited superior antibacterial efficacy than tiamulin. It was also found that compound 12 had no significant inhibitory effect on the proliferation of RAW264.7 cells. Compound 12 was further evaluated in CYP450 inhibition assay and showed moderate inhibitory effect on CYP3A4 (IC = 3.95 μM). Moreover, seven candidate compounds showed different affinities with the 50S ribosome by SPR measurement. Subsequently, binding of compound 12 and 20 to the 50S ribosome was further investigated by molecular modeling. Three strong hydrogen bonds were formed through the interaction of compound 12 and 20 with 50S ribosome. The binding free energy of compound 12 and 20 with the ribosome was calculated to be -10.7 kcal/mol and -11.66 kcal/mol, respectively.
一系列新型截短侧耳素衍生物被设计和合成，以 1,2,4-三唑为连接子，在温和条件下与苯甲酰氯类似物相连。采用肉汤稀释法测试了合成衍生物对 4 株金黄色葡萄球菌（MRSA ATCC 43300、ATCC 29213、AD3 和 144）的体外抗菌活性。大多数合成衍生物表现出很强的活性，22-（3-氨基-2-（4-甲基苯甲酰基）-1,2,4-三唑-5-基）-硫代乙酰基）-22-去氧截短侧耳素（化合物 12）被发现是对 MRSA 最有效的抗菌衍生物（MIC = 0.125 μg/mL）。此外，时间杀伤曲线表明，化合物 12 对体外 MRSA 有一定的抑制作用。进一步利用 MRSA 感染小鼠大腿模型评价化合物 12 的体内抗菌活性。化合物 12 对 MRSA 的抗菌疗效优于泰妙菌素。还发现化合物 12 对 RAW264.7 细胞的增殖没有明显的抑制作用。进一步对化合物 12 进行 CYP450 抑制试验，结果表明其对 CYP3A4 有中等抑制作用（IC = 3.95 μM）。此外，通过 SPR 测量，七种候选化合物显示出与 50S 核糖体不同的亲和力。随后，通过 SPR 测量进一步研究了化合物 12 和 20 与 50S 核糖体的结合情况。化合物 12 和 20 通过与 50S 核糖体的相互作用形成了三个强氢键。化合物 12 和 20 与核糖体的结合自由能分别计算为-10.7 kcal/mol 和-11.66 kcal/mol。
