Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity.

With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase， and based on previous structural and computational information， in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds， such as the 2-hydroxybenzamido derivatives 29， 31， and 32， and the 4-aminophenyl derivative 54， which inhibited viral growth in the low micromolar range (EC?=?0.18-1.2?μM) at no toxic concentrations (CC?>?250?μM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors， confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents.