Discovery of 2-aminoquinolone acid derivatives as potent inhibitors of SARS-CoV-2

Young Sup Shin; Jun Young Lee; Sangeun Jeon; Subeen Myung; Hyun June Gong; Seungtaek Kim; Hyoung Rae Kim; Lak Shin Jeong; Chul Min Park

doi:10.1016/j.bmcl.2023.129214

Discovery of 2-aminoquinolone acid derivatives as potent inhibitors of SARS-CoV-2

Bioorg Med Chem Lett. 2023 Apr 1:85:129214. doi: 10.1016/j.bmcl.2023.129214. Epub 2023 Mar 2.

Authors

Young Sup Shin¹, Jun Young Lee¹, Sangeun Jeon², Subeen Myung³, Hyun June Gong⁴, Seungtaek Kim², Hyoung Rae Kim⁵, Lak Shin Jeong⁶, Chul Min Park⁷

Affiliations

¹ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
² Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
³ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34114, Republic of Korea.
⁴ Department of Chemistry, Chungnam National University, Daejeon 34134, Republic of Korea.
⁵ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
⁶ Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: [email protected].
⁷ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 34114, Republic of Korea. Electronic address: [email protected].

Abstract

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to threaten human health and create socioeconomic problems worldwide. A library of 200,000 small molecules from the Korea Chemical Bank (KCB) were evaluated for their inhibitory activities against SARS-CoV-2 in a phenotypic-based screening assay to discover new therapeutics to combat COVID-19. A primary hit of this screen was the quinolone structure-containing compound 1. Based on the structure of compound 1 and enoxacin, which is a quinolone-based antibiotic previously reported to have weak activity against SARS-CoV-2, we designed and synthesized 2-aminoquinolone acid derivatives. Among them, compound 9b exhibited potent antiviral activity against SARS-CoV-2 (EC₅₀ = 1.5 µM) without causing toxicity, while having satisfactory in vitro PK profiles. This study shows that 2-aminoquinolone acid 9b provides a promising new template for developing anti-SARS-CoV-2 entry inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology
COVID-19*
Humans
Molecular Docking Simulation
Pandemics
Protease Inhibitors
SARS-CoV-2*

Substances

aminoquinolone
Antiviral Agents
Protease Inhibitors