Tautomerism and Rotamerism of Favipiravir and Halogenated Analogues in Solution and in the Solid State

Abstract

Favipiravir is an important selective antiviral against RNA-based viruses, and currently, it is being repurposed as a potential drug for the treatment of COVID-19. This type of chemical system presents different carboxamide-rotameric and hydroxyl-tautomeric states, which could be essential for interpreting its selective antiviral activity. Herein, the tautomeric 3-hydroxypyrazine/3-pyrazinone pair of favipiravir and its 6-substituted analogues, 6-Cl, 6-Br, 6-I, and 6-H, were fully investigated in solution and in the solid state through ultraviolet–visible, 1H nuclear magnetic resonance, infrared spectroscopy, and X-ray diffraction techniques. Also, a study of the gas phase was performed using density functional theory calculations. In general, the keto–enol balance in these 3-hydroxy-2-pyrazinecarboxamides is finely modulated by external and internal electrical variations via changes in solvent polarity or by replacement of substituents at position 6. The enol tautomer was prevalent in an apolar environment, whereas an increase in the level of the keto tautomer was favored by an increase in solvent polarity and, even moreso, with a strong hydrogen-donor solvent. Keto tautomerization was favored either in solution or in the solid state with a decrease in 6-substituent electronegativity as follows: H ≫ I ≈ Br > Cl ≥ F. Specific rotameric states based on carboxamide, “cisoide” and “transoide”, were identified for the enol and keto tautomer, respectively; their rotamerism is dependent on the tautomerism and not the aggregation state.

In vitro antiviral activity of favipiravir and its 6‐ and 3‐O‐substituted derivatives against coronavirus: Acetylation leads to improvement of antiviral activity

“…The compounds were divided into two groups: (i) 3-hydroxy-2pyrazinecarboxamide functionalized at the 6-position by halogens (F, Cl, Br, and I) and a hydrogen atom yielding five derivatives 1a-e [28] and (ii) 3-hydroxy-2-pyrazinecarboxamide functionalized at the 3-Omoiety using removal groups (acetyl, triflate, benzyl, methane-sulfonyl) yielding four new derivatives 2a-e. The first group of compounds, 1a-e, was prepared previously by our group following reported strategies, with a few modifications.…”

“…The first group of compounds, 1a-e, was prepared previously by our group following reported strategies, with a few modifications. [28] Meanwhile, compounds 2a-e were prepared for the first time herein using reported strategies, with a few modifications, as depicted in Scheme 1a. Compounds 2a and 2b were prepared by coupling with triflic anhydride in the presence of triethylamine in dichloromethane at room temperature for 1 h under a nitrogen atmosphere.…”

“…Compound 2c was prepared following the same procedure mentioned above using methanesulfonic chloride for 3 h. Meanwhile, compound 2d was synthesized by coupling with excess acetic anhydride in the presence of phosphoric acid at 60°C for 1 h. [30] Finally, compound 2e was prepared by coupling favipiravir with excess benzyl chloride by heating (80°C) for 5 h (Scheme 1b). [28] Spectroscopic data of the synthesized compounds, F I G U R E 1 Mechanism pathway for the formation of the active favipiravir-ribofuranosyl-5B-triphosphate (favipiravir-RTP) metabolite from the keto-tautomer of favipiravir. [23] The image was adapted with permission from the American Society for Clinical Pharmacology and Therapeutics, Clin.…”

Investigation of Antimicrobial, Cytotoxic, and Larvicidal Activities of Favipiravir

“…Favipiravir is a pyrazine carboxamide derivative (6-fluoro-3-hydroxy-2pyrazinecarboxamide) and a broad-spectrum antiviral drug approved in Japan for the treatment of influenza. [21] Favipiravir is an antiviral drug that is expected to have a therapeutic effect on COVID-19 infection. Teratogenicity and hyperuricemia are known as the main side effects of favipiravir, but little is known about other side effects.…”

“…[22] In addition to the inhibition of influenza virus, favipiravir shows inhibitory effects on a wide range of RNA viruses, such as arenavirus, bunyavirus, flavivirus, and filoviruses causing hemorrhagic fever. [21] Favipiravir is a purine nucleoside. Prymidines and their compounds also have antiviral, antibacterial, and antifungal proporties.…”