L-高丝氨酸连接的双氢青蒿素及氟喹诺酮缀合分子研究  

Hybrid molecules of dihydroartemisinin with fluoroquinolones linked by L-homoserine have anti-tuberculosis and lipid-lowering effects

作　　者：潘建芳 孙晓丽 范莉 唐雪梅[2] 罗鹏 杨大成 PAN Jian-fang;SUN Xiao-li;FAN Li;TANG Xue-mei;LUO Peng;YANG Da-cheng(Key Laboratory of Applied Chemistry of Chongqing Municipality,Institute of Bioorganic and Medicinal Chemistry,School of Chemistry and Chemical Engineering,Southwest University,Chongqing 400715,China;School of Life Science,Southwest University,Chongqing 400715,China)

机构地区：[1]西南大学化学化工学院,重庆市高校应用化学重点实验室,生物有机与药物化学研究所,重庆400715 [2]西南大学生命科学学院,重庆400715

出　　处：《药学学报》2020年第9期2157-2169,共13页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金应急管理项目(NSFC21542003);中央高校基本业务费项目(XDJK2019C043)。

摘　　要：基于多靶点药物设计思路以及双氢青蒿素和氟喹诺酮药物分子的活性优势,采用活性片段拼接思路,设计合成了18个未见文献报道的L-高丝氨酸连接的双氢青蒿素及氟喹诺酮缀合物,测试了抗结核分支杆菌和降血脂靶点PCSK9的体外活性。生物活性测试结果表明,大多数目标分子具有抗结核活性,其中5个化合物对于复制状态的结核分枝杆菌的抑制率在80%以上,3个化合物对于非复制状态的结核分枝杆菌(H37Rv)的抑制率高于50%;构效关系分析发现TM2(Boc保护)较TM1(Cbz保护)系列化合物具有更好的抗结核活性。13个目标分子的PCSK9抑制活性高于72%,且TM1-3达到了92.30%,显示良好的抑制活性。物理参数计算表明,所有分子几乎无毒;构毒关系分析可知,TM2系列分子的安全性几乎都高于TM1,可能与目标分子中氨基酸保护基有关,这对后续分子的设计和改构有一定的参考意义。本研究开创了L-高丝氨酸残基作为多靶点药物分子联结结构的先例。Eighteen dihydroartemisinin-fluoroquinolone molecules conjugated with L-homoserine were designed and synthesized using fragmented drug splicing approaches.The in vitro activities of the synthesized conjugates against Mycobacterium tuberculosis(MTB)and the lipid-lowering target PCSK9 were evaluated.The bioassay test results showed that most of the synthesized molecules had anti-tuberculosis(anti-TB)activity.Five compounds showed greater than 80%inhibitory activity against MTB in the replication state and three compounds exhibited more than 50%inhibitory activity against H37Rv in the non-replication state.A structure-activity relationship analysis demonstrated that TM2 series compounds(Boc protection)have better anti-TB activity than TM1 series compounds(Cbz protection).There were 13 compounds with strong inhibitory activity toward PCSK9(>73%)and TM1-3compounds reached 92%.The determination of physical parameters showed that all the molecules are largely nontoxic.The structure-toxicity relationship analysis showed that the safety of TM2 is higher than that of TM1 in all parameters,perhaps related to the protecting group of the amino acid in the target molecule,and provides new ideas for the design and structural modification of subsequent molecules.This study sets a precedent for L-homoserine as a linking structural unit in multi-target drug molecules.

关 键 词：双氢青蒿素 氟喹诺酮 抗结核活性 PCSK9抑制活性 高丝氨酸 

分 类 号：R916[医药卫生—药学]