Synthesis and first evaluation of new favipiravir analogs based on cyclic amidrazones scaffolds

In a context of (re-)emergence of viral infections, there is a strong appeal to propose new therapeutic alternatives which will also help to anticipate the renewal of our armamentarium currently showing limitations in drug resistance. Favipiravir has shown a broad spectrum of activity against a great variety of viruses (West Nile virus, Norovirus, encephalitis viruses, arenaviruses, (ortho)bunya-virus, Ebola virus, coronavirus and influenza viruses). In the course of new generation of efficient antivirals, the design of original nucleos(t)idic inhibitors is crucial and our strategy was inspired by a diversification of the outstanding favipiravir scaffold by taking advantage of the cyclic amidrazone cores as bioisoteric compounds. Our work discloses comparative binding mode studies to evaluate this relevant opportunity of scaffold hopping. Our original strategies allowed the production of two new series of 1,4,5,6-tetrahydro-1,2,4-triazine-6-carboxamides and 5-carboxamide-triazinone analogs. Their first evaluation as anti-influenza candidates was explored and showed a significant effect for one intermediate compound. However, the four final carboxamide compounds did not display the expected activity and might have limitations to afford the corresponding metabolized and active compound. Having in hand attractive building blocks, these new scaffolds should also prompt our scientific community to bring more structural variety within nucleosidic analogs or other drug candidates.