Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors

Jun Young Lee; Young Sup Shin; Jihye Lee; Sunoh Kwon; Young-Hee Jin; Min Seong Jang; Seungtaek Kim; Jong Hwan Song; Hyoung Rae Kim; Chul Min Park

doi:10.1016/j.bmcl.2020.127472

Identification of 4-anilino-6-aminoquinazoline derivatives as potential MERS-CoV inhibitors

Bioorg Med Chem Lett. 2020 Oct 15;30(20):127472. doi: 10.1016/j.bmcl.2020.127472. Epub 2020 Aug 8.

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 Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, South Korea; Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, 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; KM Application Center, Korea Institute of Oriental Medicine, Dong-gu, Daegu 41062, South Korea.
⁵ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, South Korea; Department of Non-Clinical Studies, Korea Institute of Toxicology, Yuseong-gu, Daejeon 34114, South Korea.
⁶ Center for Convergent Research of Emerging Virus Infection (CEVI), Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, South Korea. Electronic address: [email protected].

Abstract

New therapies for treating coronaviruses are urgently needed. A series of 4-anilino-6-aminoquinazoline derivatives were synthesized and evaluated to show high anti-MERS-CoV activities. N⁴-(3-Chloro-4-fluorophenyl)-N⁶-(3-methoxybenzyl)quinazoline-4,6-diamine (1) has been identified in a random screen as a hit compound for inhibiting MERS-CoV infection. Throughout optimization process, compound 20 was found to exhibit high inhibitory effect (IC₅₀ = 0.157 μM, SI = 25) with no cytotoxicity and moderate in vivo PK properties.

Keywords: 4-Anilino-6-aminoquinazoline; Coronavirus; Inhibitor; MERS-CoV; Optimization.

Publication types

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

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / pharmacokinetics
Aniline Compounds / pharmacology*
Aniline Compounds / toxicity
Animals
Antiviral Agents / chemical synthesis
Antiviral Agents / pharmacokinetics
Antiviral Agents / pharmacology*
Antiviral Agents / toxicity
Cell Line
Chlorocebus aethiops
Cricetulus
Humans
Mice
Microbial Sensitivity Tests
Middle East Respiratory Syndrome Coronavirus / drug effects*
Molecular Structure
Quinazolines / chemical synthesis
Quinazolines / pharmacokinetics
Quinazolines / pharmacology*
Quinazolines / toxicity
Rats
Structure-Activity Relationship

Substances

Aniline Compounds
Antiviral Agents
Quinazolines