黄病毒科感染,例如由丙型肝炎(HCV)和登革病毒(DENVs)引起的,代表全球健康风险。感染者有慢性肝衰竭或出血热的危险,如果不治疗,两者都可能是致命的。热带寄生虫布氏锥虫和克氏锥虫在撒哈拉以南非洲和拉丁美洲造成巨大的社会经济负担。抗HCV化疗有严重的不良反应,费用昂贵,而登革热没有临床批准的治疗方法。抗寄生虫药物往往是有毒的,难以使用,治疗失败被广泛报道。迫切需要新的化学疗法。根据我们之前的研究,我们已经对先导化合物V进行了结构修饰,目的是生产具有抗病毒和杀锥虫活性的衍生物。设计了新的螺碳环取代的乙内酰脲类似物,合成,并测试了针对三种HCV基因型的抗病毒活性(1b,3a,4a),DENV,黄热病毒(YFV),和两个锥虫物种(T.Brucei,T.克鲁兹)。优化是成功的,并导致化合物具有显着的抗病毒和杀锥虫活性和出色的选择性。进行了一些修改以进一步研究结构-活性关系(SAR),并确认亲脂性和构象自由度的关键作用。
Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted
hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure-activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom.