Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure–Activity Relationship, and X-ray Structural Studies,Journal of Medicinal Chemistry

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Indole Chloropyridinyl Ester-Derived SARS-CoV-2 3CLpro Inhibitors: Enzyme Inhibition, Antiviral Efficacy, Structure–Activity Relationship, and X-ray Structural Studies
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-09-16 , DOI: 10.1021/acs.jmedchem.1c01214
Arun K Ghosh ₁ , Jakka Raghavaiah ₁ , Dana Shahabi ₁ , Monika Yadav ₁ , Brandon J Anson ₂ , Emma K Lendy ₃ , Shin-Ichiro Hattori ₄ , Nobuyo Higashi-Kuwata ₄ , Hiroaki Mitsuya _{4,

5,

6} , Andrew D Mesecar _{2,

3}

Affiliation

Here, we report the synthesis, structure–activity relationship studies, enzyme inhibition, antiviral activity, and X-ray crystallographic studies of 5-chloropyridinyl indole carboxylate derivatives as a potent class of SARS-CoV-2 chymotrypsin-like protease inhibitors. Compound 1 exhibited a SARS-CoV-2 3CLpro inhibitory IC₅₀ value of 250 nM and an antiviral EC₅₀ value of 2.8 μM in VeroE6 cells. Remdesivir, an RNA-dependent RNA polymerase inhibitor, showed an antiviral EC₅₀ value of 1.2 μM in the same assay. Compound 1 showed comparable antiviral activity with remdesivir in immunocytochemistry assays. Compound 7d with an N-allyl derivative showed the most potent enzyme inhibitory IC₅₀ value of 73 nM. To obtain molecular insight into the binding properties of these molecules, X-ray crystal structures of compounds 2, 7b, and 9d-bound to SARS-CoV 3CLpro were determined, and their binding properties were compared.

中文翻译：

吲哚氯吡啶酯衍生的 SARS-CoV-2 3CLpro 抑制剂：酶抑制、抗病毒功效、构效关系和 X 射线结构研究

在此，我们报告了 5-氯吡啶基吲哚羧酸酯衍生物作为一类有效的 SARS-CoV-2 胰凝乳蛋白酶样蛋白酶抑制剂的合成、构效关系研究、酶抑制、抗病毒活性和 X 射线晶体学研究。化合物1在 VeroE6 细胞中表现出 SARS-CoV-2 3CLpro 抑制 IC ₅₀值为 250 nM，抗病毒 EC ₅₀值为 2.8 μM。Remdesivir 是一种 RNA 依赖性 RNA 聚合酶抑制剂，在同一测定中显示出抗病毒 EC _{50值为 1.2 μM。}在免疫细胞化学测定中，化合物1显示出与瑞德西韦相当的抗病毒活性。具有N-烯丙基衍生物的化合物7d显示出最有效的酶抑制IC ₅₀值为73nM。为了从分子角度了解这些分子的结合特性，确定了与 SARS-CoV 3CLpro 结合的化合物2、7b和9d的 X 射线晶体结构，并比较了它们的结合特性。

更新日期：2021-10-14

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