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Background: Influenza is a seasonal disease that affects millions of people every year and has a significant economic impact. Vaccines are the best strategy to fight this viral pathology, but they are not always available or administrable, prompting the search for antiviral drugs. RNA-dependent RNA polymerase (RdRp) recently emerged as a promising target because of its key role in viral replication and its high conservation among viral strains. Discussion: This review presents an overview of the most interesting RdRp inhibitors that have been discussed in the literature since 2000. Compounds already approved or in clinical trials and a selection of inhibitors endowed with different scaffolds are described, along with the main features responsible for their activity. Results: RdRp inhibitors are emerging as a new strategy to fight viral infections and the importance of this class of drugs has been confirmed by the FDA approval of baloxavir marboxil in 2018. Despite the complexity of the RdRp machine makes the identification of new compounds a challenging research topic, it is likely that in the coming years, this field will attract the interest of a number of academic and industrial scientists because of the potential strength of this therapeutic approach.

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.

Btk is a tyrosine kinase dysregulated in several B-cell malignancies and autoimmune diseases, and this has given rise to a search for Btk inhibitors. Nevertheless, only one Btk inhibitor, ibrutinib, has been approved to date, although other compounds are currently being evaluated in clinical trials or in preclinal stages. Area covered: This review, after a brief introduction on Btk and its inhibitors already in clinical trials, focusses on pyrrolo[2,3-d]pyrimidine derivatives patented in the last five years as Btk inhibitors. Indeed, the pyrrolo[2,3-d]pyrimidine scaffold, being a deaza-isostere of adenine, the nitrogenous base of ATP, is an actively pursued target for Btk inhibitors. The patent literature since 2012 have been extensively investigated, pointing out the general features of the patented compounds and, when it is possible, their mechanism of action. Expert opinion: The recently patented pyrrolo[2,3-d]pyrimidines, acting as reversible or irreversible inhibitors, showed a very interesting in vitro activity. For this reason, the development of compounds endowed with this scaffold could afford a significant impact in the search for drug candidates for the treatment of immune diseases or B-cell malignancies.