Sriram Dharmarajan, Yogeeswari Perumal, Srichakravarthy Narasimharaghavan, Bal Tanushree Ratan
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani 333031, India.
Bioorg Med Chem Lett. 2004 Mar 8;14(5):1085-7. doi: 10.1016/j.bmcl.2004.01.007.
A series of prodrugs of stavudine were synthesized in an effort to enhance spectrum of chemotherapeutic properties for the effective treatment of HIV/AIDS. The 5'-OH function of stavudine was esterified with ciprofloxacin, norfloxacin, isoniazide, pyrazinamide, piperazine and dimethylamine acetic acid. The anti-HIV-1 activity of the esters was determined in CEM cell line and stavudine ester bearing piperazine acetic acid was found to be the most potent compound with a selective index of >15,723. Stavudine prodrug bearing ciprofloxacin and norfloxacin acetic acid showed 100% inhibition against Mycobacterium tuberculosis H(37)Rv at 6.25 microg/mL. The prodrugs also exhibited antibacterial activity against 24 pathogenic bacteria. In vitro hydrolysis of the various esters in human plasma indicated that these agents were relatively stable toward plasma esterases with t(1/2) ranging from 20-240 min.
为了增强化学治疗特性的范围以有效治疗艾滋病毒/艾滋病，合成了一系列司他夫定的前药。司他夫定的5'-OH官能团用环丙沙星、诺氟沙星、异烟肼、吡嗪酰胺、哌嗪和二甲胺乙酸进行酯化。在CEM细胞系中测定了这些酯的抗HIV-1活性，发现带有哌嗪乙酸的司他夫定酯是最有效的化合物，选择性指数>15,723。带有环丙沙星和诺氟沙星乙酸的司他夫定前药在6.25μg/mL时对结核分枝杆菌H(37)Rv显示出100%的抑制作用。这些前药还对24种病原菌表现出抗菌活性。各种酯在人血浆中的体外水解表明，这些药物对血浆酯酶相对稳定，半衰期范围为20 - 240分钟。
