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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.

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.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Pismataro MC,Felicetti T,Bertagnin C,Nizi MG,Bonomini A,Barreca ML,Cecchetti V,Jochmans D,De Jonghe S,Neyts J,Loregian A,Tabarrini O,Massari S

doi

10.1016/j.ejmech.2021.113494

keywords:

["1,2,4-triazolo[1,5-a]pyrimidines","Antiviral agents","Influenza polymerase","Influenza virus","PA-PB1 interaction","Protein-protein interaction","SARS-CoV-2"]

subject

Has Abstract

pub_date

2021-10-05 00:00:00

pages

113494

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(21)00343-3

journal_volume

221

pub_type

杂志文章

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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.