新型青蒿素衍生物改善溶解度及其抗结核活性研究  

Enhancement of water solubility and anti-tuberculosis activities by a novel artemisinin derivative

作　　者：张宁[1] 刘洋[2] 李晔[2] 胡平[1,2] ZHANG Ning;LIU Yang;LI Ye;HU Ping(School of Pharmaceutical Sciences,Chongqing University,Chongqing 401331,China;Shanxi Chinese Medicine Research Institute,Xi'an 710003,China)

机构地区：[1]重庆大学药学院,重庆401331 [2]陕西省中医药研究院,陕西西安710003

出　　处：《药学学报》2019年第1期36-40,共5页Acta Pharmaceutica Sinica

基　　金：陕西省中药创新药物研究中心项目(2017YWZX-02)

摘　　要：青蒿素及其衍生物已被证明具有抗结核菌活性,但其在水中的低溶解度影响了其药效及适用剂型的制备。本研究设计合成了一个新型的青蒿素衍生物,通过琥珀酸将精氨酸链接到青蒿素分子上,既解决了青蒿素溶解度低的问题,又进一步利用精氨酸对细菌细胞壁的扰乱作用,增强了细菌对精氨酸所携带青蒿素的摄取,从而提高了青蒿素的抗菌效果。结果显示,与青蒿素原型药物相比,合成的青蒿素衍生物A-2和A-3在水中的溶解度提高了约19.8～27.8倍。体外细胞毒性证明,质量浓度为1 mg·mL^(-1)的化合物A-3对人白血病单核巨噬细胞无明显细胞毒性。体外抗结核菌实验表明,目标化合物A-2和A-3最低抑菌浓度(MIC)分别为20和10μg·mL^(-1),相对青蒿素提高了5～10倍。细胞内抑菌实验表明, A-3在较低浓度(100和200μg·mL^(-1))下就可显著抑制THP-1巨噬细胞的胞内细菌生长(P<0.05或P<0.01),其作用强于100μg·mL^(-1)青蒿素(P<0.05)。说明A-3是具有成药潜力的抗结核先导化合物。Artemisinin and its derivatives have been proved for their anti-tuberculosis activities, despite itslow water solubility which hampered its efficacy and corresponding formulation development. In this study wedesigned and synthesized a novel artemisinin analog by conjugating an arginine through a succinic acid linker.This design not only enhanced the water solubility of the artemisinin, but also increased the efficacy of themolecule towards tuberculosis bacteria due to disruption by arginine. The results showed that the solubility ofthe synthesized derivatives A-2 and A-3 increased 19.8-27.8 folds compared to artemisinin. In vitro cytotoxicityexperiment showed that compound A-3 had negligible toxicity to THP-1 cells up to 1 mg · mL^-1, the minimalinhibitory concentration(MIC) of A-2 and A-3 was 20 and 10 μg · mL^-1, respectively, which was 5 or 10 timeslower than that of artemisinin. Intracellular bacteria inhibition experiment showed that compound A-3 at lowerconcentrations such as 100 or 200 μg · mL^-1 significantly inhibited the growth of tuberculosis bacteria(P<0.05 orP<0.01), which efficacy was stronger than artemisinin at the concentration of 100 μg · mL^-1. These results stronglysuggested that compound A-3 was a potential anti-tuberculosis lead compound.

关 键 词：青蒿素 衍生物 结核病 精氨酸 溶解度 

分 类 号：R943[医药卫生—药剂学]