2-苄基氨基喹唑啉-4(3)-酮衍生物作为严重急性呼吸综合征冠状病毒2潜在治疗药物的合成及生物学评价
Synthesis and biological evaluation of 2-benzylaminoquinazolin-4(3)-one derivatives as a potential treatment for SARS-CoV-2.
作者信息
Lee Jun Young, Shin Young Sup, Jeon Sangeun, Lee Se In, Cho Jung-Eun, Myung Subeen, Jang Min Seong, Kim Seungtaek, Song Jong Hwan, Kim Hyoung Rae, Park Chul Min
机构信息
Center for Convergent Research of Emerging Virus Infection (CEVI) Korea Research Institute of Chemical Technology Yuseong-gu, Daejeon South Korea.
Zoonotic Virus Laboratory Institut Pasteur Korea Seongnam-si Gyeonggi-do South Korea.
出版信息
Bull Korean Chem Soc. 2022 Mar;43(3):412-416. doi: 10.1002/bkcs.12470. Epub 2022 Jan 23.
Abstract
Despite the continuing global crisis caused by coronavirus disease 2019 (COVID-19), there is still no effective treatment. Therefore, we designed and synthesized a novel series of 2-benzylaminoquinazolin-4(3)-one derivatives and demonstrated that they are effective against SARS-CoV-2. Among the synthesized derivatives, 7-chloro-2-(((4-chlorophenyl)(phenyl)methyl)amino)quinazolin-4(3)-one (Compound ) showed highest anti-SARS-CoV-2 activity, with a half-maximal inhibitory concentration value greater than that of remdesivir (IC = 4.2 μM vs. 7.6 μM, respectively), which gained urgent approval from the U.S. Food and Drug Administration. In addition, Compound showed good results in various assays measuring metabolic stability, human ether a-go-go, Cytochromes P450 (CYPs) inhibition, and plasma protein binding (PPB), and showed better solubility and pharmacokinetics than our previous work.
摘要
尽管2019冠状病毒病（COVID-19）引发的全球危机仍在持续，但仍没有有效的治疗方法。因此，我们设计并合成了一系列新型的2-苄基氨基喹唑啉-4(3)-酮衍生物，并证明它们对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）有效。在合成的衍生物中，7-氯-2-(((4-氯苯基)(苯基)甲基)氨基)喹唑啉-4(3)-酮（化合物 ）表现出最高的抗SARS-CoV-2活性，其半数最大抑制浓度值高于瑞德西韦（IC 分别为4.2 μM和7.6 μM），瑞德西韦已获得美国食品药品监督管理局的紧急批准。此外，化合物 在各种测量代谢稳定性、人醚-去极化相关基因、细胞色素P450（CYPs）抑制和血浆蛋白结合（PPB）的试验中均显示出良好的结果，并且比我们之前的工作表现出更好的溶解性和药代动力学。
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