A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro.
1,4,4-trisubstituted piperidine
SARS-CoV-2
Ugi reaction
antiviral compound
coronavirus
main protease
Journal
Pharmaceuticals (Basel, Switzerland)
ISSN: 1424-8247
Titre abrégé: Pharmaceuticals (Basel)
Pays: Switzerland
ID NLM: 101238453
Informations de publication
Date de publication:
18 Aug 2022
18 Aug 2022
Historique:
received:
26
07
2022
revised:
15
08
2022
accepted:
16
08
2022
entrez:
26
8
2022
pubmed:
27
8
2022
medline:
27
8
2022
Statut:
epublish
Résumé
There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure-activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2'-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (M
Identifiants
pubmed: 36015168
pii: ph15081021
doi: 10.3390/ph15081021
pmc: PMC9416004
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : MICINN
ID : PID2019-104070RB-C21
Organisme : MICINN
ID : PID2019-104070RB-C22
Organisme : Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas
ID : CSIC-PIE-201980E100
Organisme : Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas
ID : CSIC-PIE-201980E028
Organisme : European Union's Innovative Medicines Initiative (IMI) [Corona Accelerated R&D in Europe (CARE) project]
ID : 101005077
Organisme : Fundació La Marató de TV3, Spain
ID : 201832-30
Organisme : Fundació La Marató de TV3, Spain
ID : 202135-30
Organisme : FWO Research Foundation Flanders
ID : 1S66321N
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