Geisman Alexander N, Valuev-Elliston Vladimir T, Ozerov Alexander A, Khandazhinskaya Anastasia L, Chizhov Alexander O, Kochetkov Sergey N, Pannecouque Christophe, Naesens Lieve, Seley-Radtke Katherine L, Novikov Mikhail S
Department of Pharmaceutical & Toxicological Chemistry, Volgograd State Medical University, Pavshikh Bortsov Sq., 1, Volgograd 400131, Russia.
Engelhardt Institute of Molecular Biology, Russian Academy of Science, Vavilov Str., 32, Moscow 119991, Russia.
Bioorg Med Chem. 2016 Jun 1;24(11):2476-2485. doi: 10.1016/j.bmc.2016.04.010. Epub 2016 Apr 5.
A series of 1,6-bis[(benzyloxy)methyl]uracil derivatives combining structural features of both diphenyl ether and pyridone types of NNRTIs were synthesized. Target compounds were found to inhibit HIV-1 reverse transcriptase at micro- and submicromolar levels of concentrations and exhibited anti-HIV-1 activity in MT-4 cell culture, demonstrating resistance profile similar to first generation NNRTIs. The synthesized compounds also showed profound activity against influenza virus (H1N1) in MDCK cell culture without detectable cytotoxicity. The lead compound of this assay appeared to exceed rimantadine, amantadine, ribavirin and oseltamivir carboxylate in activity. The mechanism of action of 1,6-bis[(benzyloxy)methyl]uracils against influenza virus is currently under investigation.
合成了一系列1,6-双[(苄氧基)甲基]尿嘧啶衍生物，其结合了二苯醚型和吡啶酮型非核苷类逆转录酶抑制剂（NNRTIs）的结构特征。发现目标化合物在微摩尔和亚微摩尔浓度水平下可抑制HIV-1逆转录酶，并在MT-4细胞培养中表现出抗HIV-1活性，显示出与第一代NNRTIs相似的耐药谱。合成的化合物在MDCK细胞培养中还表现出对甲型流感病毒（H1N1）的显著活性，且未检测到细胞毒性。该试验的先导化合物在活性上似乎超过了金刚乙胺、金刚烷胺、利巴韦林和奥司他韦羧酸盐。目前正在研究1,6-双[(苄氧基)甲基]尿嘧啶对流感病毒的作用机制。
