Tang Sheng, Peng Zong-Gen, Li Ying-Hong, Zhang Xin, Fan Tian-Yun, Jiang Jian-Dong, Wang Yan-Xiang, Song Dan-Qing
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Chem Cent J. 2017 Sep 29;11(1):94. doi: 10.1186/s13065-017-0327-8.
12N-benzyl matrinic acid analogues had been identified to be a novel scaffold of anti-HCV agents with a specific mechanism, and the representative compound 1 demonstrated a moderate anti-HCV activity. The intensive structure-activity relationship of this kind of compounds is explored so as to obtain anti-HCV candidates with good druglike nature.
Taking compound 1 as the lead, 32 compounds (of which 27 were novel) with diverse structures on the 11-side chain, including methyl matrinate, matrinol, matrinic butane, (Z)-methyl Δ-matrinic crotonate derivatives were synthesized and evaluated for their anti-HCV activities. Among all the compounds, matrinol 7a demonstrated potential potency with a greatly improved SI value of 136. Pharmacokinetic studies of 7a showed the potential for oral administration that would allow further in vivo safety studies. The free hydroxyl arm in 7a made it possible to prepare pro-drugs for the potential in the treatment of HCV infection.
27 novel 12N-substituted matrinol derivatives were prepared. The SAR study indicated that the introduction of electron-donating substitutions on the benzene ring was helpful for the anti-HCV activity, and the unsaturated 11-side chain might not be favorable for the activity. This study provided powerful information on further strategic optimization and development of this kind of compounds into a novel family of anti-HCV agents. Graphical abstract Matrinol derivatives as a class of novel anti-HCV agents.
12N-苄基苦参酸类似物已被鉴定为具有特定作用机制的新型抗丙型肝炎病毒（HCV）药物骨架，代表性化合物1表现出中等的抗HCV活性。为了获得具有良好类药性质的抗HCV候选药物，对这类化合物的构效关系进行了深入研究。
以化合物1为先导，合成了32个在11-侧链上具有不同结构的化合物（其中27个为新化合物），包括苦参酸甲酯、苦参醇、苦参丁烷、（Z）-Δ-苦参酸巴豆酸甲酯衍生物，并对其抗HCV活性进行了评价。在所有化合物中，苦参醇7a表现出潜在活性，其SI值大幅提高至136。7a的药代动力学研究表明其具有口服给药的潜力，这将允许进一步进行体内安全性研究。7a中的游离羟基臂使其有可能制备前药用于治疗HCV感染。
制备了27个新型的12N-取代苦参醇衍生物。构效关系研究表明，在苯环上引入供电子取代基有助于抗HCV活性，而不饱和的11-侧链可能不利于活性。本研究为这类化合物进一步的策略优化以及开发成为新型抗HCV药物家族提供了有力信息。图形摘要：苦参醇衍生物作为一类新型抗HCV药物。
