Tang Sheng, Li Yu-Huan, Cheng Xin-Yue, Li Ying-Hong, Wang Hui-Qiang, Kong Lan-Ying, Zhang Xin, Jiang Jian-Dong, Song Dan-Qing
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
State Key Laboratory of Bioactive Substance & Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Future Med Chem. 2016 Apr;8(5):495-508. doi: 10.4155/fmc-2015-0019. Epub 2016 Feb 12.
MATERIALS & METHODS: Fifty-one novel 12N-substituted matrinic acid derivatives were synthesized and evaluated for their anti-coxsackievirus B3 activities.
Structure-activity relationship studies revealed that the 11-side chain could be determinant for the selectivity index by adjusting overall lipophilicity, and 11-butane was the best one for both potency and druggability. The optimized 35d showed the broad-spectrum anti-coxsackieviruse effects, an excellent pharmacokinetics and a good safety profile. More importantly, it displayed a potential effect for the pleconaril-resistant coxsackievirus B3 as well. Its mode of action is targeting on the viral transcription and translation stage, a different mechanism from that of pleconaril.
Thus, we considered that 35d is a promising anti-enteroviral candidate for the treatment of various diseases infected with coxsackieviruses.
合成了51种新型12N-取代的苦参酸衍生物，并对其抗柯萨奇病毒B3活性进行了评估。
构效关系研究表明，11-侧链可通过调节整体亲脂性来决定选择性指数，11-丁烷对于效力和可药用性而言是最佳的。优化后的35d显示出广谱抗柯萨奇病毒作用、优异的药代动力学和良好的安全性。更重要的是，它对耐普来可那利的柯萨奇病毒B3也显示出潜在作用。其作用方式靶向病毒转录和翻译阶段，这与普来可那利的作用机制不同。
因此，我们认为35d是一种有前景的抗肠道病毒候选药物，可用于治疗由柯萨奇病毒感染引起的各种疾病。
