Department of Chemistry, Saint Louis University, Saint Louis, MO, 63103, USA.
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA.
Eur J Med Chem. 2022 Aug 5;238:114443. doi: 10.1016/j.ejmech.2022.114443. Epub 2022 May 14.
We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 μM and displayed EC values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R and R of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N-hydroxypyridones as HSV therapeutics.
我们之前曾表明，抗真菌药物环吡酮胺能有效抑制单纯疱疹病毒（HSV）-1 和 HSV-2 的复制。鉴于对核苷酸类似物治疗有抗药性的 HSV 株以及核苷酸类似物疗效不完全，必须探索新的抑制化合物，以便有潜力用于治疗 HSV 感染。在本研究中，我们分析了 44 种源自环吡酮胺核心结构的化合物，以评估其对 HSV 的抑制活性。其中 13 种衍生化合物在 1 μM 时对 HSV-2 的抑制作用超过 1000 至约 100000 倍，EC 值低于阿昔洛韦，且细胞毒性低，表明其具有很强的治疗潜力。通过结构比较，我们还为环吡酮及其衍生物的各种结构基序对疗效的重要性提供了证据，即环吡酮核心结构中 R 和 R 的疏水性基团。与环吡酮类似，代表性类似物具有一定的口服生物利用度，但在体内迅速清除。总之，这些结果将指导 N-羟基吡啶酮类化合物作为 HSV 治疗药物的进一步开发。
