Molecules (Feb 2022)
Synthesis, Structure–Activity Relationships, and Antiviral Profiling of 1-Heteroaryl-2-Alkoxyphenyl Analogs as Inhibitors of SARS-CoV-2 Replication
- Dorothée Bardiot,
- Laura Vangeel,
- Mohamed Koukni,
- Philippe Arzel,
- Marleen Zwaagstra,
- Heyrhyoung Lyoo,
- Patrick Wanningen,
- Shamshad Ahmad,
- Linlin Zhang,
- Xinyuanyuan Sun,
- Adrien Delpal,
- Cecilia Eydoux,
- Jean-Claude Guillemot,
- Eveline Lescrinier,
- Hugo Klaassen,
- Pieter Leyssen,
- Dirk Jochmans,
- Karolien Castermans,
- Rolf Hilgenfeld,
- Colin Robinson,
- Etienne Decroly,
- Bruno Canard,
- Eric J. Snijder,
- Martijn J. van Hemert,
- Frank van Kuppeveld,
- Patrick Chaltin,
- Johan Neyts,
- Steven De Jonghe,
- Arnaud Marchand
Affiliations
- Dorothée Bardiot
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Laura Vangeel
- Laboratory of Virology and Chemotherapy, KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
- Mohamed Koukni
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Philippe Arzel
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Marleen Zwaagstra
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
- Heyrhyoung Lyoo
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
- Patrick Wanningen
- Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Shamshad Ahmad
- Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DDI 5EH, UK
- Linlin Zhang
- Institute of Molecular Medicine, University of Lübeck, 23562 Lübeck, Germany
- Xinyuanyuan Sun
- Institute of Molecular Medicine, University of Lübeck, 23562 Lübeck, Germany
- Adrien Delpal
- Laboratory Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Centre National de la Recherche Scientifique (CNRS), Aix Marseille University, CEDEX 9, 13288 Marseille, France
- Cecilia Eydoux
- Laboratory Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Centre National de la Recherche Scientifique (CNRS), Aix Marseille University, CEDEX 9, 13288 Marseille, France
- Jean-Claude Guillemot
- Laboratory Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Centre National de la Recherche Scientifique (CNRS), Aix Marseille University, CEDEX 9, 13288 Marseille, France
- Eveline Lescrinier
- Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
- Hugo Klaassen
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Pieter Leyssen
- Laboratory of Virology and Chemotherapy, KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
- Dirk Jochmans
- Laboratory of Virology and Chemotherapy, KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
- Karolien Castermans
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Rolf Hilgenfeld
- Institute of Molecular Medicine, University of Lübeck, 23562 Lübeck, Germany
- Colin Robinson
- Drug Discovery Unit, School of Life Sciences, University of Dundee, Dundee DDI 5EH, UK
- Etienne Decroly
- Laboratory Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Centre National de la Recherche Scientifique (CNRS), Aix Marseille University, CEDEX 9, 13288 Marseille, France
- Bruno Canard
- Laboratory Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Centre National de la Recherche Scientifique (CNRS), Aix Marseille University, CEDEX 9, 13288 Marseille, France
- Eric J. Snijder
- Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Martijn J. van Hemert
- Department of Medical Microbiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
- Frank van Kuppeveld
- Virology Section, Infectious Disease and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands
- Patrick Chaltin
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- Johan Neyts
- Laboratory of Virology and Chemotherapy, KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
- Steven De Jonghe
- Laboratory of Virology and Chemotherapy, KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium
- Arnaud Marchand
- Centre for Innovation and Stimulation of Drug Discovery (CISTIM), Gaston Geenslaan 2, 3001 Leuven, Belgium
- DOI
- https://doi.org/10.3390/molecules27031052
- Journal volume & issue
-
Vol. 27,
no. 3
p. 1052
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
