4.7 Article

1,2,4-Triazolo[1,5-a]pyrimidines: Efficient one-step synthesis and functionalization as influenza polymerase PA-PB1 interaction disruptors

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出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113494

关键词

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

资金

  1. Ministero dell'Istruzione, dell'Universita e della Ricerca-MIUR, PRIN 2017 [2017BMK8JR]
  2. Fondazione Cassa Risparmio Perugia -Ricerca Scientifica e Tecnologica 2019: Giovani ricercatori: risorsa per il territorio [3FCRPG19_SM]
  3. Associazione Italiana per la Ricerca sul Cancro, AIRC [IG18855]
  4. British Society for Antimicrobial Chemotherapy, UK [BSAC-2018-0064]
  5. Ministero dell'Istruzione, dell'Universita e della Ricerca, PRIN 2017 [2017KM79NN]
  6. Fondazione Cassa di Risparmio di Padova e Rovigo Bando Ricerca Covid-2019 [55777 2020.0162]
  7. Hercules Foundation [ZW13-02]
  8. Rega Foundation, KU Leuven [ZW13-02]

向作者/读者索取更多资源

The study identified 1,2,4-triazolo[1,5-a] pyrimidine (TZP) as a suitable scaffold for developing anti-influenza virus compounds, with compound 22 showing high activity. Furthermore, the research highlighted the potential of TPZ scaffold in the search for anti-coronavirus agents.
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 mM) and anti-IAV activity (EC50 = 16 mM) 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 mM, high-lighting the potential of the TPZ scaffold in the search for anti-CoV agents. (C) 2021 Elsevier Masson SAS. All rights reserved.

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