Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, E41013 Seville, Spain.
J Med Chem. 2020 Mar 26;63(6):3142-3160. doi: 10.1021/acs.jmedchem.9b01950. Epub 2020 Feb 28.
The effective treatment of adenovirus (HAdV) infections in immunocompromised patients still poses great challenges. Herein, we reported our continued efforts to optimize a series of salicylamide derivatives as potent inhibitors of HAdV infection. Of these, nine compounds (, , , , , , , , and ) showed significantly improved anti-HAdV activities with nanomolar to submicromolar IC values and high selectivity indexes (SI > 100), indicating better safety windows, compared to those of the lead compound niclosamide. Our mechanistic assays suggest that compounds , , and exert their activities in the HAdV entry pathway, while compounds and likely target the HAdV DNA replication, and , and inhibit later steps after DNA replication. Given the broad anti-viral activity profile of niclosamide, these derivatives may also offer therapeutic potential for other viral infections.
在免疫功能低下的患者中，有效治疗腺病毒（HAdV）感染仍然面临巨大挑战。在此，我们报告了我们持续努力优化一系列水杨酰胺衍生物，以获得有效的 HAdV 感染抑制剂。其中，有 9 种化合物（、、、、、、、和）表现出显著增强的抗 HAdV 活性，其纳摩尔至亚毫摩尔的 IC 值和高选择性指数（SI > 100）表明与先导化合物氯硝柳胺相比，具有更好的安全性窗。我们的机制研究表明，化合物、、在 HAdV 进入途径中发挥作用，而化合物、可能靶向 HAdV DNA 复制，化合物、和抑制 DNA 复制后的后续步骤。鉴于氯硝柳胺广泛的抗病毒活性谱，这些衍生物也可能为其他病毒感染提供治疗潜力。
