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1,2,4-Triazolo[1,5-a]pyrimidines: Efficient one-step synthesis and functionalization as influenza polymerase PA-PB1 interaction disruptors
- Publication Year :
- 2021
- Publisher :
- Elsevier Masson s.r.l., 2021.
-
Abstract
- In the search for new anti-influenza virus (IV) compounds, we have identified the 1,2,4-triazolo[1,5-a]pyrimidine (TZP) as a very suitable scaffold to obtain compounds able to disrupt IV RNA-dependent RNA polymerase (RdRP) PA-PB1 subunits heterodimerization. In this work, in order to acquire further SAR insights for this class of compounds and identify more potent derivatives, we designed and synthesized additional series of analogues to investigate the role of the substituents around the TZP core. To this aim, we developed four facile and efficient one-step procedures for the synthesis of 5-phenyl-, 6-phenyl- and 7-phenyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidines, and 2-amino-5-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol. Two analogues having the ethyl carboxylate moiety at the C-2 position of the TZP were also prepared in good yields. Then, the scaffolds herein synthesized and two previous scaffolds were functionalized and evaluated for their anti-IAV activity, leading to the identification of compound 22 that showed both anti-PA-PB1 (IC50 = 19.5 μM) and anti-IAV activity (EC50 = 16 μM) at non-toxic concentrations, thus resulting among the most active TZP derivatives reported to date by us. A selection of the synthesized compounds, along with a set of in-house available analogues, was also tested against SARS-CoV-2. The most promising compound 49 from this series displayed an EC50 value of 34.47 μM, highlighting the potential of the TPZ scaffold in the search for anti-CoV agents. ispartof: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY vol:221 ispartof: location:France status: published
- Subjects :
- 1,2,4-triazolo[1,5-a]pyrimidines
Antiviral agents
Influenza polymerase
Influenza virus
PA-PB1 interaction
Protein-protein interaction
SARS-CoV-2
01 natural sciences
Madin Darby Canine Kidney Cells
chemistry.chemical_compound
RNA polymerase
Chlorocebus aethiops
Drug Discovery
Moiety
Polymerase
0303 health sciences
biology
Chemistry
General Medicine
Influenza A virus
Pyrimidine
RNA-dependent RNA polymerase
Microbial Sensitivity Tests
Protein–protein interaction
Viral Proteins
03 medical and health sciences
Dogs
Animals
Humans
Carboxylate
Vero Cells
030304 developmental biology
Pharmacology
010405 organic chemistry
Organic Chemistry
Triazoles
RNA-Dependent RNA Polymerase
Combinatorial chemistry
0104 chemical sciences
HEK293 Cells
Pyrimidines
4-triazolo[1
Drug Design
5-a]pyrimidines
biology.protein
Surface modification
Protein Multimerization
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....4be29729f2bec0ed7028ba24640ab26b