tetano
Editor, Senior Moderator
Molecules
. 2022 Feb 4;27(3):1052.
doi: 10.3390/molecules27031052.
Synthesis, Structure-Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication
Dorothée Bardiot[SUP] 1 [/SUP], Laura Vangeel[SUP] 2 [/SUP], Mohamed Koukni[SUP] 1 [/SUP], Philippe Arzel[SUP] 1 [/SUP], Marleen Zwaagstra[SUP] 3 [/SUP], Heyrhyoung Lyoo[SUP] 3 [/SUP], Patrick Wanningen[SUP] 4 [/SUP], Shamshad Ahmad[SUP] 5 [/SUP], Linlin Zhang[SUP] 6 [/SUP], Xinyuanyuan Sun[SUP] 6 [/SUP], Adrien Delpal[SUP] 7 [/SUP], Cecilia Eydoux[SUP] 7 [/SUP], Jean-Claude Guillemot[SUP] 7 [/SUP], Eveline Lescrinier[SUP] 8 [/SUP], Hugo Klaassen[SUP] 1 [/SUP], Pieter Leyssen[SUP] 2 [/SUP], Dirk Jochmans[SUP] 2 [/SUP], Karolien Castermans[SUP] 1 [/SUP], Rolf Hilgenfeld[SUP] 6 9 [/SUP], Colin Robinson[SUP] 5 [/SUP], Etienne Decroly[SUP] 7 [/SUP], Bruno Canard[SUP] 7 [/SUP], Eric J Snijder[SUP] 4 [/SUP], Martijn J van Hemert[SUP] 4 [/SUP], Frank van Kuppeveld[SUP] 3 [/SUP], Patrick Chaltin[SUP] 1 10 [/SUP], Johan Neyts[SUP] 2 [/SUP], Steven De Jonghe[SUP] 2 [/SUP], Arnaud Marchand[SUP] 1 [/SUP]
Affiliations
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry. A systematic structure-activity relationship (SAR) study demonstrated that a 3- or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity.
Keywords: 1,2,4-oxadiazole; 1-heteroaryl-2-alkoxyphenyl analogs; COVID-19; SARS-CoV-2.
. 2022 Feb 4;27(3):1052.
doi: 10.3390/molecules27031052.
Synthesis, Structure-Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication
Dorothée Bardiot[SUP] 1 [/SUP], Laura Vangeel[SUP] 2 [/SUP], Mohamed Koukni[SUP] 1 [/SUP], Philippe Arzel[SUP] 1 [/SUP], Marleen Zwaagstra[SUP] 3 [/SUP], Heyrhyoung Lyoo[SUP] 3 [/SUP], Patrick Wanningen[SUP] 4 [/SUP], Shamshad Ahmad[SUP] 5 [/SUP], Linlin Zhang[SUP] 6 [/SUP], Xinyuanyuan Sun[SUP] 6 [/SUP], Adrien Delpal[SUP] 7 [/SUP], Cecilia Eydoux[SUP] 7 [/SUP], Jean-Claude Guillemot[SUP] 7 [/SUP], Eveline Lescrinier[SUP] 8 [/SUP], Hugo Klaassen[SUP] 1 [/SUP], Pieter Leyssen[SUP] 2 [/SUP], Dirk Jochmans[SUP] 2 [/SUP], Karolien Castermans[SUP] 1 [/SUP], Rolf Hilgenfeld[SUP] 6 9 [/SUP], Colin Robinson[SUP] 5 [/SUP], Etienne Decroly[SUP] 7 [/SUP], Bruno Canard[SUP] 7 [/SUP], Eric J Snijder[SUP] 4 [/SUP], Martijn J van Hemert[SUP] 4 [/SUP], Frank van Kuppeveld[SUP] 3 [/SUP], Patrick Chaltin[SUP] 1 10 [/SUP], Johan Neyts[SUP] 2 [/SUP], Steven De Jonghe[SUP] 2 [/SUP], Arnaud Marchand[SUP] 1 [/SUP]
Affiliations
- PMID: 35164317
- DOI: 10.3390/molecules27031052
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subsequent hit-to-lead optimization campaigns, we conducted a high-throughput screening of a 160 K compound library against SARS-CoV-2, yielding a 1-heteroaryl-2-alkoxyphenyl analog as a promising hit. Antiviral profiling revealed this compound was active against various beta-coronaviruses and preliminary mode-of-action experiments demonstrated that it interfered with viral entry. A systematic structure-activity relationship (SAR) study demonstrated that a 3- or 4-pyridyl moiety on the oxadiazole moiety is optimal, whereas the oxadiazole can be replaced by various other heteroaromatic cycles. In addition, the alkoxy group tolerates some structural diversity.
Keywords: 1,2,4-oxadiazole; 1-heteroaryl-2-alkoxyphenyl analogs; COVID-19; SARS-CoV-2.