合成和评估具有SARS-CoV-2抗病毒活性的9-氨基亚克里丁
Thane Jones1, Natalia Monakhova2, Florence Guivel-Benhassine3
1Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, North Carolina 27606, United States.
ACS omega
|November 6, 2023
概括
两种抗疟疾药物显示对SARS-CoV-2的活性. 研究人员修改了9-氨基亚克里丁基架,识别了具有强大的抗病毒作用和中度细胞毒性的新型类似物,提供了新的COVID-19治疗线索.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
背景情况:
- 很少有小分子直接准SARS-CoV-2.
- 现有的抗疟疾药物,如皮罗纳里丁和奎纳克林,显示出抗病毒活性.
- 皮罗纳里丁还可以抑制SARS-CoV-2PLpro,这是一个关键的病毒酶.
研究的目的:
- 探索对抗SARS-CoV-2的9-氨基亚克里丁支架的结构-活性关系.
- 识别具有改善抗病毒活性和有利的安全概况的新型类似物.
- 将现有的药物架构重新用于COVID-19治疗.
主要方法:
- 使用传统的药用化学技术.
- 合成和评估了新的9 - 氨基亚克里丁类型.
- 在相关细胞系 (A549 + ACE2,U2-OS ACE2 GFP) 中评估了*体外*的抗病毒活性和细胞毒性.
主要成果:
- 鉴定出具有强烈的*体外*活性 (IC50<1.0μM) 的新型类型对抗SARS-CoV-2.
- 在新型类似物中达到中度细胞毒性 (CC50>4.0μM).
- 化合物7g,9c和7e的选择性指数 (SI) > 10.
- 化合物9c表现出最强的活性 (IC50 ≤0.42μM,CC50 ≥4.41μM,SI>10).
结论:
- 9-氨基亚克里丁基架可以被修改为产生强大的SARS-CoV-2抑制剂.
- 新型类似物显示为COVID-19药物开发的化合物具有前途.
- 化合物9c是进一步研究的一个特别强大的候选物.
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