In this study, we systematically investigated the electronic structure, spectroscopic (nuclear magnetic resonance, infrared, Raman, electron ionization mass spectrometry, UV-Vis, circular dichroism, and emission) properties, and tautomerism of halogenated favipiravir compounds (fluorine, chlorine, and bromine) from a computational perspective. Additionally, the effects of hydration on the proton transfer mechanism of the tautomeric forms of the halogenated favipiravir compounds are discussed. Our results suggest that spectroscopic properties allow for the elucidation of such tautomeric forms. As is well-known, the favipiravir compound has excellent antiviral properties and hence was recently tested for the treatment of new coronavirus (SARS-CoV-2). Through in silico modeling, in the current study, we evaluate the role of such tautomeric forms in order to consider the effect of drug-metabolism in the inhibition process of the main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 virus. According to the molecular docking, all halogenated compounds presented a better interaction energy than the co-crystallized active ligand (-3.5 kcal mol-1) in the viral RdRp, in both wild-type (-6.3 to -6.5 kcal mol-1) and variant (-5.4 to -5.6 kcal mol-1) models. The variant analyzed for RdRp (Y176C) decreases the affinity of the keto form of the compounds in the active site, and prevented the ligands from interacting with RNA. These findings clearly indicated that all these compounds are promising as drug candidates for this molecular target.

Center for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Department of Chemistry Federal University of Lavras CEP 37200 000 Lavras Minas Gerais Brazil

Post graduation Program in Materials Science and Engineering and Laboratory of Nanotechnology and Computational Chemistry Federal Technological University of Paraná Avenida dos Pioneiros 3131 86036 370 Londrina Paraná Brazil

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