Design, synthesis and biological evaluation of 2-aminoquinazolin-4(3H)-one derivatives as potential SARS-CoV-2 and MERS-CoV treatments

Jun Young Lee; Young Sup Shin; Sangeun Jeon; Se In Lee; Soojin Noh; Jung-Eun Cho; Min Seong Jang; Seungtaek Kim; Jong Hwan Song; Hyoung Rae Kim; Chul Min Park

doi:10.1016/j.bmcl.2021.127885

Design, synthesis and biological evaluation of 2-aminoquinazolin-4(3H)-one derivatives as potential SARS-CoV-2 and MERS-CoV treatments

Bioorg Med Chem Lett. 2021 May 1:39:127885. doi: 10.1016/j.bmcl.2021.127885. Epub 2021 Mar 2.

Authors

Affiliations

¹ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, South Korea.
² Zoonotic Virus Laboratory, Institut Pasteur Korea, Seongnam-si, Gyeonggi-do 13488, South Korea.
³ Department of Non-Clinical Studies, Korea Institute of Toxicology, Yuseong-gu, Daejeon 34114, South Korea.
⁴ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, South Korea; Korea University of Science and Technology, Daejeon 34114, South Korea. Electronic address: [email protected].

Abstract

Despite the rising threat of fatal coronaviruses, there are no general proven effective antivirals to treat them. 2-Aminoquinazolin-4(3H)-one derivatives were newly designed, synthesized, and investigated to show the inhibitory effects on SARS-CoV-2 and MERS-CoV. Among the synthesized derivatives, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (9g) and 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4 (3H)-one (11e) showed the most potent anti-SARS-CoV-2 activities (IC₅₀ < 0.25 μM) and anti-MERS-CoV activities (IC₅₀ < 1.1 μM) with no cytotoxicity (CC₅₀ > 25 μM). In addition, both compounds showed acceptable results in metabolic stabilities, hERG binding affinities, CYP inhibitions, and preliminary PK studies.

Keywords: 2-aminoquinazolinone; Antiviral; Coronavirus; MERS-CoV; SARS-CoV-2.

Publication types

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

MeSH terms

Animals
Antiviral Agents / chemical synthesis*
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19 / virology
COVID-19 Drug Treatment
Cell Line
Cell Survival / drug effects
Coronavirus Infections / drug therapy
Coronavirus Infections / virology
Cytochrome P-450 Enzyme System / chemistry
Cytochrome P-450 Enzyme System / metabolism
Drug Design*
Half-Life
Humans
Inhibitory Concentration 50
Mice
Microsomes / metabolism
Middle East Respiratory Syndrome Coronavirus / drug effects*
Middle East Respiratory Syndrome Coronavirus / isolation & purification
Quinazolinones / chemistry
Quinazolinones / metabolism
Quinazolinones / pharmacology*
Quinazolinones / therapeutic use
Rats
SARS-CoV-2 / drug effects*
SARS-CoV-2 / isolation & purification
Structure-Activity Relationship

Substances

Antiviral Agents
Quinazolinones
Cytochrome P-450 Enzyme System