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JOURNAL OF THE IRANIAN CHEMICAL SOCIETY, vol.19, no.1, pp.85-94, 2022 (SCI-Expanded)
In this work we report structural and computational studies of favipiravir, which is now used as a drug for COVID-19 treatment. The molecule is completely flat and stabilized by an intramolecular O-H center dot center dot center dot O hydrogen bond, yielding a six-membered pseudo-aromatic ring. The aromaticity index of this pseudo-aromatic ring was found to be 0.748, while the same indix for the pyrazine ring in favipiravir was found to be 0.954. The crystal packing of favipiravir is mainly constructed through intermolecular N-H center dot center dot center dot O, N-H center dot center dot center dot N and C-H center dot center dot center dot O hydrogen bonds, yielding a 3D supramolecular framework with a zst topology defined by the point symbol of (6(5)center dot 8). The crystal structure of favipiravir is further stabilized by weak C-F center dot center dot center dot F-C intermolecular type II dihalogen interactions, yielding a 1D supramolecular polymeric chain. More than 80% of the total Hirshfeld surface area for favipiravir is occupied by H center dot center dot center dot H/C/N/O/F and C center dot center dot center dot N/O contacts. Energy frameworks have been calculated to additionally analyze the overall crystal packing. It was established that the structure of favipiravir is mainly characterized by the dispersion energy framework followed by the less significant electrostatic energy framework contribution. Finally, by using density functional theory (DFT) calculations and the quantum theory of atoms in molecules, we have assigned the interaction energy of each hydrogen bond, which can be helpful to develop scoring functions to be used in force fields/docking calculations.