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Synthesis and biological evaluation of a library of hybrid derivatives as inhibitors of influenza virus PA-PB1 interaction.

Research paper by Ilaria I D'Agostino, Ilaria I Giacchello, Giulio G Nannetti, Anna Lucia AL Fallacara, Davide D Deodato, Francesca F Musumeci, Giancarlo G Grossi, Giorgio G Palù, Ylenia Y Cau, Iuni Margaret IM Trist, Arianna A Loregian, Silvia S Schenone, Maurizio M Botta

Indexed on: 25 Aug '18Published on: 25 Aug '18Published in: European Journal of Medicinal Chemistry



Abstract

The limited treatment options against influenza virus along with the growing public health concerns regarding the continuous emergence of drug-resistant viruses make essential the development of new anti-flu agents with novel mechanisms of action. One of the most attractive targets is the interaction between two subunits of the RNA-dependent RNA polymerase, PA and PB1. Herein we report the rational design of hybrid compounds starting from a 3-cyano-4,6-diphenylpyridine scaffold recently identified as disruptor of PA-PB1 interactions. Guided by the previously reported SAR data, a library of amino acid derivatives was synthesized. The biological evaluation led to the identification of new PA-PB1 inhibitors, that do not show appreciable toxicity. Molecular modeling shed further lights on the inhibition mechanism of these compounds. Copyright © 2018. Published by Elsevier Masson SAS.

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