INTRODUCTION
T-705 (favipiravir), a fluorinated pyrazinecarboxamide was initially developed against influenza virüs[1]. T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, an inhibitor of the influenza virüs with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). T-705 exhibits activity against type B and C viruses with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively.[2] Favipiravir acts as a purine analogue that selectively inhibits viral RdRps.[3] In addition to its potent anti-influenza activity, favipiravir has shown activity against a wide range of other RNA viruses, including enteroviruses, bunyaviruses, filoviruses, norovirus, arenaviruses, flaviviruses rhabdoviruses, and alphaviruses.[4-6]They reported that favipiravir had potent antiviral activity against henipaviruses and showed that In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice-daily oral or once-daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virüs.[7] In February 2020, the drug favipiravir began to be studied in China for its experimental treatment in COVID-19 (new coronavirus) disease, which appeared in China.[8] Parlak et al.[9]investigated the adsorption between favipiravir and undoped or silicon doped C60 fullerenes and to assess their possible usage as drug delivery vehicles and also they studied the possible interaction mechanism of C20 and Si-doped C20 fullerenes with favipiravir molecule.[10] They reported structural analysis of favipiravir performed by exploring tautomers formations. They reported that four tautomers could be possible for favipiravir and their stability could be different regarding the values of total energy and also reported that the results indicated that the structure given in Figure 1 was the most stable structure and the next one is F1 by 5 kcal/mol difference in the stability level.[11]
FIGURE 1
In very recent studies, favipiravir has been studied for experimental treatments of COVID-19, where it is recommended as an effective drug recently. [12]
Previous studies have shown that quantum chemical calculations can very well evaluate molecular properties.[13-16] Over the past two decades, there has been a great deal of interest in studying the tautomerism of heterocyclic compounds to ensure that the effect of tautomerism on the chemical and biological properties of molecules can be determined. These structures and tautomers can occur if the energy required for tautomer formation is provided by other sources, such as intermolecular interactions and binding, and may be important in recognizing such structures before exploring their activity in the biological environment. [10]
This study aims to investigate two different structures (A and B) and three tautomers of structure A and two tautomers of structure B and transition states between the tautomers and conformer A and B in different environments as a quantum chemical. Besides, the temperature addiction of the thermodynamic parameters such as heat capacity (Cv), entropy (S), zero-point energy, heat capacity at constant pressure was calculated at B3LYP /6-311G(d,p) level in the gas phase for A3 form.
MATERIALS AND METHODS
Gaussian 09 program.[17] was used for all DFT calculations. Possible structures (Figure 2) in the gas phase, and different media have been analyzed by performing density functional theory (DFT) calculations at the B3LYP/6-311G(d,p) theoretical level. Frequency computations based on the same geometry optimization method were used to confirm the nature of the stationary points. Frequency calculations characterized all stationary points. The reaction pathway was determined by following the IRC procedure.[18,19] In addition, the effects of four solvents, ethanol, DMF, DMSO and water were studied through the self-consistent reaction-field (SCRF) method based one conductor-like polarisable continuum model (CPCM), which is often considered one of the most successful solvation models.[20]
The Polarizable continuity model (PCM) proposed by Born, Kirkwood and Onsager is an extension of the solvent reaction field models presented for charge distributions in space. PCM uses a more realistic shape of the void, simulates the dielectric response with separate charges on the void surface, and contains nonpolar additives to the solution.[21]
The electronic energies, NLO properties, the energy of the highest occupied molecular orbital (EHOMO), and the lowest unoccupied molecular orbital (ELUMO) of the energy were computed. Also, some parameters related to HOMO and LUMO energies such as chemical hardness (h), chemical softness (S), electronegativity (χ), chemical potential (μ) and electrophilicity index (w) were computed. Nonlinear optical (NLO) properties such as dipole moment (µ), mean polarizability (αtotal), the anisotropy of the polarizability (∆α) and first hyperpolarizability (β) were computed with the B3LYP/6-311G(d,p) theoretical level.
RESULT and DISCUSSION
Two different structures were considered (A and B). The features of three tautomers of structure A and two tautomers of structure B were examined. The transition states between the tautomers of structure A in gas and solvent phases were examined, and also the transition states of structure A and B were examined.
The optimized possible molecular conformations of favipiravir numbering of the atoms, and its transition states forms with the sum of electronic and zero-point Energies calculated using B3LYP/6311 G(d,p) theoretical method in the gas phase were given in Figure 2.
FIGURE 2
No imaginary frequencies were found in the calculated vibrational spectra of the stable A1, A2, A3, B1, B2 form of favipiravir while a single imaginary stretching frequency was found for each Transition State (TS). The value of imaginary frequencies are -1893 cm-1 for TS1, -515 cm-1 for TS2, -1903 cm-1 for TS3, in gas phase. The energies for the A1, A2, A3, B1, and B2 form of favipiravir and transition between A1 with A2, A2 with A3, and A3 with B1 are summarized in Table 1 for different media. The energies are sensitive to the gas phase and solvent used. On the other hand, transition states are characterized by higher energies compared to the other form. It is clear that the calculated values of the energies depend on the solvent media used.
Accordingly the energy is -381253.07 kcal/mol for A1 form, -381240.80 kcal/mol for A2 form and -381239.30 kcal/mol for A3 form. A1, A2 and A3 form are tautomer form each other. A1 is more stable than the others. A3 and B1 are different conformers of favipiravir molecule. B1 conformer is stable than A3 conformer however is less stable than A1 and A2 tautomer forms in gas phase and different media (Table 1). The order of stability of A1, A2, A3 tautomers studied in the gas phase and solvent media is A1 > A2 > A3.