Investigation of favipiravir complexation through double iron chelation: experimental and theoretical insights

Abstract

Considering the dramatic health and economic period that the world experienced during the COVID-19 pandemic, finding new drugs for the treatment of this disease is still a great scientific concern. Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide) is an important selective antiviral against RNA-based viruses, like SARS‐CoV‐2 virus causing COVID-19 disease, and has recently attracted considerable interest. The behavior of Favipiravir in various solvents including water, methanol, ethanol, isopropanol, methyl tert-butyl ether (MTBE), and dimethyl sulfoxide (DMSO) was investigated. A novel iron (III) complex compound derived from FAV as the ligand was synthesized. Subsequently, the newly synthesized complex was subjected to various analytical and spectroscopic techniques, including UV and infrared spectroscopy, mass spectrometry, stoichiometry analysis using the molar ratio method, and thermogravimetric analysis (TG–DTA). It was observed that the keto/enolic equilibrium of favipiravir is influenced by the choice of diluent, with the enol tautomer being the predominant form. Further analysis revealed that the isolated metal complex exhibits a tetrahedral geometry. The complexation reaction is more favorable in a protic medium than in an aprotic one, primarily due to the easier deprotonation in protic environments. Additionally, the molecular structures of the free ligand and its metal complex compound were optimized using density functional theory (DFT) simulations. This study offers valuable insights into the quantum chemical properties related to the structure. The simulation indicates significant chemical stability and a pronounced electrophilic character of the iron complex. Overall, these findings contribute to a deeper understanding of the interaction dynamics and stability of favipiravir's metal complexes.

Graphical abstract