J Med Chem. 2023 Aug 10;66(15):10746-10760. doi: 10.1021/acs.jmedchem.3c00924. Epub 2023 Jul 28.
Dengue (DENV) and Zika (ZIKV) viruses are important human pathogens, causing ∼100 million symptomatic infections each year. These infections carry a 20-fold increased incidence of serious neurological diseases, such as microcephaly in newborns (for ZIKV) and Guillain-Barré syndrome. Moreover, DENV can develop serious and possibly life-threatening dengue hemorrhagic fever in certain patients. Patients recovered from one of the four serotypes of DENV are still susceptible to other serotypes with a higher likelihood of serious disease because of antibody-dependent enhancement. Except for mosquito control, there have been no antiviral drugs to prevent and treat ZIKV/DENV infections. Phenotypic screening found that 2,3,6-trisubstituted quinazolinone compounds are novel inhibitors of ZIKV replication. Fifty-four analogues were synthesized, and their structure-activity relationships are discussed. Additional testing shows that compounds , , and exhibited broad and potent activities against ZIKV and DENV with EC values as low as 86 nM with no significant cytotoxicity to mammalian cells.
登革热（DENV）和寨卡（ZIKV）病毒是重要的人类病原体，每年导致约 1 亿例有症状感染。这些感染使严重神经系统疾病（如新生儿小头畸形（ZIKV）和格林-巴利综合征）的发病率增加了 20 倍。此外，DENV 可导致某些患者出现严重且可能危及生命的登革出血热。从 DENV 的四种血清型之一中恢复的患者仍然容易受到其他血清型的感染，因为抗体依赖性增强作用会导致更严重的疾病。除了蚊子控制外，目前还没有抗病毒药物来预防和治疗 ZIKV/DENV 感染。表型筛选发现，2,3,6-三取代喹唑啉酮化合物是 ZIKV 复制的新型抑制剂。合成了 54 个类似物，并讨论了它们的构效关系。进一步的测试表明，化合物、和表现出针对 ZIKV 和 DENV 的广泛而强大的活性，EC 值低至 86 nM，对哺乳动物细胞没有明显的细胞毒性。
