Favipiravir Tautomerism: A Short Theoretical Report

Antonov, L.

doi:10.26434/chemrxiv.12115620

Cited by 9 publications

(10 citation statements)

References 20 publications

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“…As reported recently, the enol tautomer of T-705 is more stable than the keto form (which is subsequently referred to as T-705K). 7 At the M05-2X/cc-pVTZ@SMD level of theory this study predicts that Gibbs energy of the enol form is 5.7 kcal/mol lower than that of the keto form at 298 K. This corresponds to an equilibrium constant of ca. 6×10 -5 , and a correspondingly small equilibrium concentration of the keto tautomer is expected in solution.…”

Section: Manuscriptmentioning

confidence: 83%

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Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

Silva

2020

Preprint

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Favipiravir (T-705) is an antiviral medication used to treat influenza. T-705 is also currently being trialled as a repurposed COVID-19 treatment. To help accelerate these efforts, this study provides important solution-phase properties of T-705 determined via computational chemistry. Density functional theory (DFT) calculations combined with the SMD continuum solvation model demonstrate that T-705 prefers the aromatic enol form in solution over the ketone tautomer. Deprotonation constants for the conjugate acids of T-705 (pKas) are then evaluated, by combining the DFT/SMD calculations with accurate G4 gas-phase basicities. These calculations indicate that T-705 is a weak base that should not significantly protonate at physiological pH. The preferential site for protonation is at the ring nitrogen ortho to the alcohol functional group (pKa ~ 7.4), followed by protonation of the oxygen on the amide side-chain at more acidic conditions (pKa ~ -9.8). Significantly, protonation of the ring nitrogen produces an acid that can deprotonate to the enol form (pKa ~ -5.1), providing a pathway for their interconversion. Finally, base-pairing of the active ribose-bound form of T-705 to cytidine and uridine is also examined. These calculations indicate that both base pairs have large binding free energies of around 4 – 5 kcal/mol, supporting previous findings that T-705 can bind with both nucleobases, leading to mis-incorporation of these pairs into viral RNA.<br>

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Section: Manuscriptmentioning

confidence: 83%

“…Recent calculations show that the enol form is considerably more stable than the ketone form. 7 However, there is little information available on the protomers of the T-705 tautomers and their relative stability. T-705 is a prodrug, which is metabolised in vivo to the active form -a ribosyl triphosphate (T-705RTP, Figure 2).…”

Section: Manuscriptmentioning

confidence: 99%

Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

Silva

2020

Preprint

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“…It is possible to predict the most probable tautomers of the studied dyes (azo‐hydrazone or lactam‐lactim) using quantum‐chemical calculations and analysing changes in the energy of their formation (enthalpy) 59–65 . With the use of the ab initio quantum‐chemical calculation method higher stability of the lactam form than of the lactim form was predicted 66,67 .…”

Section: Resultsmentioning

confidence: 99%

Prediction of the photofading of 1‐H or 1‐ethyl derivatives of 3‐cyano‐6‐hydroxy‐4‐methyl‐5‐(p‐X‐phenylazo)‐2‐pyridone dyes and their azo‐hydrazone tautomerism: A theoretical study

Wojciechowski

Szuster²

2022

Coloration Technology

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The lightfastness calculations for photofading of monoazo pyridone dyes were performed. For this purpose, all‐valence molecular orbital method PM3 was applied. Frontier electron density distribution on the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) was examined. The obtained parameters seem to reflect the tendency for an electrophilic attack with a singlet oxygen (1O2) atom or a nucleophilic attack with superoxide anion (O2●─) on a particular atom in a molecule. Reactivity indicators for superdelocalisability (SrEnormalN) and electron density distribution in ground and excited state were calculated. Superdelocalisabilities enable the fastness values to be explained in different chemical molecules depending on tautomeric forms in which they may occur.

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“…The contribution of tautomers, estimated from 1 H NMR spectra (at ~10 À 2 M), for 19-membered p-hydroxyazobenzocrowns, namely 19-p-OH, t-Bu-19-p-OH and Ph-19-p-OH is shown in Figure 2 and listed in Table S1. Tautomeric equilibrium in solution depends on several factors, [45][46][47][48] including obviously the structure of the molecule and the properties of its chemical…”

Section: Ph-19-p-ohmentioning

confidence: 99%

Do Phenyl Substituents Affect the Properties of Azobenzocrown Derivatives?

Wagner‐Wysiecka,

Szulc,

Luboch

et al. 2023

ChemPlusChem

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New products of photo‐ and thermal rearrangements of 19‐membered azoxybenzocrown with phenyl substituents in benzene rings in the para positions to oligooxyethylene fragments are characterized in this work. The yields of photochemical transformations depend on the solvent. Para‐hydroxyazocrown is formed with yields over 50 % in propan‐2‐ol. Ortho‐hydroxyazobenzocrown is obtained with yields up to 70 % in toluene/acetic acid mixture. Macrocyclic Ph‐20‐ester is obtained in yield 90 % under thermochemical rearrangement conditions. Structure of new hydroxyazobenzocrowns and also atypical product of rearrangements, 20‐membered ester, was confirmed by X‐ray diffraction analysis. Azophenol ←0false→ ${ \mathbin{{\stackrel{\textstyle\rightarrow} { {\smash{\leftarrow}\vphantom{_{\vbox to.5ex{\vss}}}} } }} }$ quinone‐hydrazone tautomeric equilibrium of new hydroxyazobenzocrowns and the influence of metal cations on tautomeric equilibrium was investigated using 1H NMR and UV‐Vis spectroscopy in acetonitrile. The highest value of stability constant (logK 7.25) was obtained for strontium complex of p‐hydroxyazobenzocrown. For the first time p‐hydroxyazobenzocrown was used as a chromoionophore in the receptor layer of an optical sensor. Comparative analysis with data obtained previously for series 19‐membered analogs have shown the influence of the presence of substituents in benzene rings for the course and products distribution of photo and thermal rearrangement. The effect of substituents was also discussed against the tautomeric equilibrium and metal cation complexation properties.

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Favipiravir Tautomerism: A Short Theoretical Report

Cited by 9 publications

References 20 publications

Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

Protonation, Tautomerism, and Base Pairing of the Antiviral Favipiravir (T-705)

Prediction of the photofading of 1‐H or 1‐ethyl derivatives of 3‐cyano‐6‐hydroxy‐4‐methyl‐5‐(p‐X‐phenylazo)‐2‐pyridone dyes and their azo‐hydrazone tautomerism: A theoretical study

Do Phenyl Substituents Affect the Properties of Azobenzocrown Derivatives?

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