Improved Synthesis of the Anti-SARS-CoV-2 Investigational Agent (E)-N-(4-Cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (Cyanorona-20)

Medicinal chemistry scientists` efforts and trials to discover a very potent anticoronaviral medicine specifically effective against the current frightening virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are not over yet. Synthetic organic chemistry will remain one of the most important branches in the entire drug discovery science. (E)-N-(4-Cyanobenzylidene)-6-fluoro-3-hydroxypyrazine-2-carboxamide (Cyanorona-20), a newly-discovered favipiravir analog/ derivative, is one of the promising synthetic organic compounds that displayed very strong nanomolar potencies against this fatal coronavirus, reaching an anticoronaviral-2 EC50 of nearly 450 nM or 0.45 μM. This compound was found to act against the SARS-CoV-2 mainly through the powerful inhibition of the coronaviral RNA-dependent RNA polymerase (RdRp), via competitively occupying and locking this enzyme`s major catalytic active site pocket (the suggested primary mechanism of action). Cyanorona-20 is still under progressive investigation as an attempt to continue developing it as a prospective remedy for the coronavirus disease 2019 (COVID-19). However, the previous literature synthetic procedures of Cyanorona-20 were criticized for several reasons like the harsh handling, difficult separation, small yield, and low purity. Herein in this short-communication or technical-note article, more reproducible and efficient novel synthetic method for Cyanorona-20 compound is presented, in an effort to address almost all of the problems which were accompanying the preceding methods.