Bioorganic & Medicinal Chemistry Letters ( IF 2.7 ) Pub Date : 2021-07-14 , DOI: 10.1016/j.bmcl.2021.128267 Toi Kobayashi 1 , Takumi Yasuno 1 , Kyoko Takahashi 2 , Shigeo Nakamura 2 , Tadahiko Mashino 1 , Tomoyuki Ohe 1
In the present study, we newly synthesized four types of novel fullerene derivatives: pyridinium/ethyl ester-type derivatives 3b−3l, pyridinium/carboxylic acid-type derivatives 4a, 4e, 4f, pyridinium/amide-type derivative 5a, and pyridinium/2-morpholinone-type derivative 6a. Among the assessed compounds, cis-3c, cis-3d, trans-3e, trans-3h, cis-3l, cis-4e, cis-4f, trans-4f, and cis-5a were found to inhibit HIV-1 reverse transcriptase (HIV-RT), HIV-1 protease (HIV-PR), and HCV NS5B polymerase (HCV NS5B), with IC50 values observed in the micromolar range. Cellular uptake of pyridinium/ethyl ester-type derivatives was higher than that of corresponding pyridinium/carboxylic acid-type derivatives and pyridinium/amide-type derivatives. This result might indicate that pyridinium/ethyl ester-type derivatives are expected to be lead compounds for multitargeting drugs to treat HIV/HCV coinfection.
中文翻译:
新型吡啶鎓型富勒烯衍生物作为 HIV-1 逆转录酶、HIV-1 蛋白酶和 HCV NS5B 聚合酶的多靶点抑制剂
在本研究中,我们新合成的四种类型的新颖的富勒烯衍生物的:吡啶鎓/酸乙酯型衍生物3B - 3升,吡啶鎓/羧酸类衍生物4A,4E,4F,吡啶鎓/酰胺类衍生物5A,和吡啶鎓/2-吗啉酮型衍生物6a。在评估的化合物中,cis - 3c , cis - 3d , trans - 3e , trans - 3 h , cis - 3 l , cis- 4E,顺式- 4F,反式- 4F,以及顺式-图5a被发现抑制HIV-1逆转录酶(HIV-RT),HIV-1蛋白酶(HIV-PR)和HCV NS5B聚合酶(HCV NS5B)中,用在微摩尔范围内观察到的IC 50值。吡啶鎓/乙酯类衍生物的细胞摄取高于相应的吡啶鎓/羧酸类衍生物和吡啶鎓/酰胺类衍生物。这一结果可能表明吡啶鎓/乙酯型衍生物有望成为治疗 HIV/HCV 合并感染的多靶点药物的先导化合物。