Alexandrova Liudmila, Zicari Sonia, Matyugina Elena, Khandazhinskaya Anastasia, Smirnova Tatiana, Andreevskaya Sofya, Chernousova Larisa, Vanpouille Christophe, Kochetkov Sergei, Margolis Leonid
Engelhardt Institute of Molecular Biology, Vavilova Str., 32, Moscow, 119991, Russia.
Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Antiviral Res. 2017 Sep;145:175-183. doi: 10.1016/j.antiviral.2017.07.011. Epub 2017 Jul 22.
HIV and M. tuberculosis are two intersecting epidemics making the search for new dual action drugs against both pathogens extremely important. Here, we report on the synthesis and suppressive activities of five dual-targeted HIV/TB compounds. These compounds are heterodimers of AZT, as anti-HIV molecules, and 5-substituted uracil derivatives, as anti-TB molecules. We found that these compounds inhibit the growth of M. tuberculosis and suppress the replication of HIV in human cell cultures and human lymphoid tissues ex vivo. We identified one particular heterodimer that inhibited both HIV and the drug-resistant TB strain MS-115 most potently. This compound demonstrated low toxicity and had no cytostatic effect on cells in culture, constituting an ideal candidate for future development and further in vivo testing.
艾滋病毒和结核分枝杆菌是两种相互交织的流行病，这使得寻找针对这两种病原体的新型双效药物变得极其重要。在此，我们报告了五种双靶点艾滋病毒/结核病化合物的合成及其抑制活性。这些化合物是作为抗艾滋病毒分子的齐多夫定（AZT）与作为抗结核分子的5-取代尿嘧啶衍生物的异二聚体。我们发现这些化合物在体外人细胞培养物和人淋巴组织中可抑制结核分枝杆菌的生长并抑制艾滋病毒的复制。我们鉴定出一种特别的异二聚体，它对艾滋病毒和耐药结核菌株MS-115的抑制作用最强。该化合物毒性低，对培养中的细胞无细胞抑制作用，是未来开发和进一步体内试验的理想候选物。
