key: cord-0901063-vxgynfdi
authors: Yuksel, Numan; Köse, Ahmet; Fellah, M. Ferdi
title: The supramolecularly complexes of calix[4]arene derivatives toward favipiravir antiviral drug (used to treatment of COVID-19): a DFT study on the geometry optimization, electronic structure and infrared spectroscopy of adsorption and sensing
date: 2021-06-05
journal: J Incl Phenom Macrocycl Chem
DOI: 10.1007/s10847-021-01087-1
sha: 24667e5c5edd32056cef10810ac7155d0c84a6ea
doc_id: 901063
cord_uid: vxgynfdi

While the world is in search of a vaccine that can cure COVID-19 disease, favipiravir is the most commonly used antiviral drug in the treatment of patients during the pandemic process. In this study, we investigated the host–guest interaction between the popular supramolecule calix[4]arene derivatives and the favipiravir drug by using the DFT (Density Functional Theory) method. The B3LYP hybrid method and 6-31G (d,p) basis set were utilized to determine the optimized structures of the host and guest molecules and their complexes. The negative adsorption energy (∆E) and adsorption enthalpy (∆H) calculated for the complexes formed between calix[4]arene compounds and favipiravir drug molecule mentioned that adsorption of favipiravir molecule was an exothermic process on calix[4]arene structures. On the other hand, among the calixarene derivatives in the study, Gibbs free energy change (∆G) value for the adsorption was only negative on calix[4]arene4 molecule. The infrared spectroscopy (IR) calculations were performed by examining the C=O, O–H and NH(2) vibrational frequencies to see the adsorption behavior in the favipiravir-calix[4]arene complex. After adsorption of the favipiravir molecule, HOMO–LUMO gap values decreased significantly for the structures and therefore electrical conductivity increased proportionally. In addition, sensor response factors, Fermi energy levels and workfunction changes of calix[4]arene derivatives were calculated and examined. Charge transfer between the four calix[4]arene compounds and the favipiravir molecule has occurred after adsorption. This attributes that calix[4]arene derivatives can be used as a well-suited favipiravir sensor (electronic and workfunction) and adsorbent at room temperature. Based on the calculations made to see the solvent effect on the adsorption of favipiravir it was determined that it did not affect the interaction between the drug molecule and the calix[4]arene compound too much and the adsorption energy turned into a slightly less negative value.

COVID-19 outbreaks spread rapidly all over the world. There are no vaccines and specific drugs that can be used to treat this virus so far (November 2020). Antiviral drugs such as chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir and remdesivir have been used for the treatment [1] [2] [3] . Among these antiviral drugs, favipiravir used for the treatment of influenza is noteworthy. Successful results have been obtained with the use of favipiravir, which acts as an RNA-dependent RNA inhibitor, against coronavirus [4] [5] [6] [7] [8] . Favipiravir drug can cause side effects such as diarrhea, a decrease in neutrophil count and an increase in uric acid level in the blood [5, 9] . By the widespread use of favipiravir in COVID-19 pandemic, adsorption and detection of favipiravir molecule have become more important.

The therapeutic efficacy of drug molecules in vivo depends on reaching the target area without losing their properties. During the drug molecules reach the targeted area, they can interact with biochemical substances, therefore become deactivated and lose their effectiveness [10] . Interaction during this transport may cause some problems in the delivery, absorption and excretion of drugs to the cells.

Excellent drug carriers are needed in the pharmaceutical industry to overcome these problems [11, 12] . Drug carriers increase the biodistribution by reducing the drug dosage to be used and overcome the diffusion problem between cells [13] . Macrocyclic amphiphiles exhibited some advantages in drug delivery. While these substances increase drug solubility and stability, they can also decrease drug dosage [14, 15] .

Calix [n] arenes (n = number of phenolic units), one of these macrocyclic molecules, has gained attention in recent years with its use in drug delivery and drug sensor systems [13, 16] . Calix[n]arene derivatives provide some advantages with the properties gained by their functionalization with groups such as R-SO 3 H, tert-butyl, iso-propyl, -COOH and -OH. In addition to the functional diversity of the upper and lower rims in calixarenes, their chemical stability, hydrophobic cavity, zero toxicity and controlled release profiles make calixarenes suitable for drug adsorbents and sensors [13, 17] . Moreover, these molecules have been used as drug carriers in cancer treatment. It sensitizes the tumor microenvironments and provides controlled release. In addition to these, it provides the opportunity to protect the drugs from side reactions that cause deactivation [18, 19] . Drug carrying and controlled release are associated with the adsorption of the drug on the carrier molecule. In order to understand the thermodynamic and structural properties between host and guest complex in drug adsorption, computational studies have been carried out along with experimental studies. Significant studies have been conducted to investigate these computational vehicle systems and to find new carrier materials [20] [21] [22] [23] [24] [25] [26] . Chen et al. achieved high encapsulation efficiency in the use of calix [4] arene as a carrier for paclitaxel, a cancer drug, and observed that these paclitaxel-loaded calixarenes improved the uptake of the drug into cells [27] . Athar et al. examined the host-guest relationship of calix [4] arene with lapatinib and nilotinib drugs by the semi-experimental PM3 method, and found that nilotinib (− 217.9 kJ/mol) and lapatinib (− 246.9 kJ/mol) have high binding energies onto calix [4] arene compound [28] . In a similar study reported previously, the adsorption energy value of 5-fluorouracil (5-FU) onto calix [4] arene was computed to be − 98 kJ/mol by DFT method and it was found that calix [4] arenes have appropriate adsorption properties for 5-FU at room temperature [29] .

Besides the adsorption of drugs, the sensor studies of drugs draw attention. It is important to be able to monitor and determine the effects of drugs on both humans and the environment. By its recognition ability of calixarene compounds, it has achieved successful results in the detection and separation of drugs in wastewater [30, 31] . Calixarenes are good sensors for some drugs as well as providing excellent selectivity, sensitivity and stability for long-term use [32] [33] [34] [35] . Due to their derivatizability and appropriate molecular size, calix [4] arene compounds are expected to form a good complex with the favipiravir molecule. In this study, adsorption and sensor properties of favipiravir molecule onto calix [4] arene derivatives were investigated by DFT method.

In this study, all of the quantum chemical calculations are based upon the DFT method [36] . The DFT calculations have been utilized in the Gaussian09 software [37, 38] . Using the B3LYP hybrid formalism method, which also consists of the exchange and correlation impacts, geometry optimization and energy calculations were carried out [39, 40] . B3LYP hybrid method has been stated to be one of the DFT methods for the high-quality theoretical calculation procedure for organic chemistry [41] . The basis set 6-31G(d, p) was used in calculations for all atoms. Four calix [4] arene compounds that could interact with the favipiravir molecule have been used in this research. These four compounds are derived from each other. The first of these compounds is the p-tert-butyl calix [4] arene compound which is called as calix [4] arene1 (the basic calix [4] arene compound) and the calix [4] arene2 molecule is obtained by removing of tert-butyl groups of calix [4] arene1 compound [42, 43] . The calix [4] arene3 and the calix [4] arene4 compounds are the structures formed by derivatizing calix [4] arene2 compound, and the IUPAC namings are 25,27-bis(3-mercaptopropoxy)-26,28-dihydroxy calix [4] arene and 5,17-Bis[N-(4-carboxypiperidino) methyl]-25,27-bis(3-mercaptopropoxy)-26,28-dihydroxy calix [4] arene, respectively [32] . Schematic representations of calix [4] arene compounds examined in this study are shown in Fig. 1 (drawn on the Perkinelmer-ChemOffice website).

DFT calculations were used to optimize the geometries (to obtain the equilibrium geometry (EG)) and obtain energy values for adsorption. In this analysis, zero-point energy (ZPE) corrections are included in the energy values. In this study, basis-set superposition error (BSSE) correction using the counterpoise method was not taken into account due to its very small effects [44] . Its effect on the B3LYP hybrid method was determined in the range of approximately 1-2.5 kJ/mol [45] . In addition, these values are likely to be similar for each of these systems and hence would not affect the results based on relative energies. In addition, vibrational frequency, thermal energy and thermal enthalpy values were calculated at room temperature and atmospheric pressure. The organic host calix [4] arene compounds and the favipiravir molecule were firstly optimized structurally by DFT calculations. The following energy values were calculated by subsequent equations in Gaussian software.

E is the sum of the electronic, ZPE and thermal energies, H is the sum of the thermal energies and enthalpy, G is sum of thermal enthalpy and free energy, T is the temperature used for the vibrational frequency calculations, S is the entropy and R is the global ideal gas constant. Below equation (Eq. 4) was used to calculate the relative adsorption energy, adsorption enthalpy and Gibbs free energy values. In this equation, the calix [4] arene compounds are called as the host and favipiravir molecule is called as the guest. The structure formed by host and guest molecules after adsorption is called as the complex. The inclusion processes of the host and guest molecules were handled in 1:1 ratio. In adsorption calculation, the structures were

prepared by placing the guest molecule horizontally on the upper rim region of the host molecule. Thus, every atom in the favipiravir molecule was provided to interact with the calixarene compound at the same distance, and different favipiravir configurations were not required to be calculated. In addition, the adsorption of the favipiravir molecule to the outer side of the functional group of the calix [4] arene4 compound has been calculated.

Moreover, the HOMO (highest occupied molecular orbital) and the LUMO (lowest unoccupied molecular orbital) energy values were computed by full analysis of population. Full population analysis refers to a full Mulliken population analysis that controls the printing of molecular orbitals and several types of population analysis [46] . Chemical hardness, chemical potential, electronegativity, electrophilicity, HOMO-LUMO energy gap and HOMO and LUMO energies ( HOMO and LUMO , [4] arene compounds utilized in this study for the adsorption of favipiravir molecule respectively) were calculated by using below the equations based on Koopmans approach [47, 48] .

where I ≈ − HOMO and A ≈ − LUMO .

The criteria of the convergence utilized in DFT calculations: 0.0012 rad is for gradients of root-mean-square (rms) displacement, 0.0018 bohr is for max displacement, 0.0003 hartreee/radian is for rms force and 0.00045 hartree/bohr is for max force. Furthermore, the parameters for convergence SCF used in DFT calculations; for RMS change in the density matrix and maximum change in density matrix are 0.00000001 and 0.000001, respectively. We applied GaussSum software [49] to draw the density of states (DOS) schemes. NBO atomic charges of atoms were obtained by Natural Bond Orbital (NBO) population analysis [50] . In order to reproduce experimental fundamentals, all vibrational IR frequency values have been scaled by the value of 0.9613 [51] .

The host and guest molecules were firstly optimized geometrically by DFT calculations. The EG of guest molecule (favipiravir) was determined by taking the total charge as zero and SM (Spin Multiplicity) as a singlet. The optimized geometries of calix [4] arene compounds and favipiravir molecule have been shown in Fig. 2 and the optimized geometries for the complexes of the favipiravir antiviral drug with calix [4] arene compounds are given in Fig. 3 . Here, the complexes formed between calix [4] arene1, calix [4] arene2, calix [4] arene3 and calix [4] arene4 compounds and the favipiravir molecule are named com-plex1, complex2, complex3 and complex4, respectively. In order to see the accuracy of B3LYP hybrid method and 6-31G(d, p) basis set used in DFT calculations, calix [4] arene1 compound was compared with experimental data. In a study previously reported in the literature [52] , the length of C Ar -C bond length and C Ar -C-C Ar bond angle (C Ar = the phenol's ortho position carbon) in methylene [4] arene1 compound were given as 1.51 Å and 113.9°, respectively. And in this study, these values were calculated as 1.52 Å, 113.7°, respectively. The energy values for favipiravir adsorption onto calix [4] arene structures were listed in Table 1 . When the adsorption energy values and adsorption enthalpy values for the complex formation of favipiravir and calix [4] arene compounds were examined, negative values were obtained for all complexes. This result attributes that the adsorptions of the favipiravir molecule on the complexes are an exothermic process. The adsorption energy (∆E) and enthalpy (∆H) for complex4 were calculated as − 40.6 kJ/ mol and − 43.0 kJ/mol, respectively. The reason why the best adsorption values belong to complex4 is the presence of − OH groups in the upper rim region of calix [4] arene4 compound. Because hydrogen bonds between -OH groups in calix [4] arene4 compound and -OH and -NH 2 groups in favipiravir molecule strengthen adsorption. Due to their negative binding energies, it is possible that hydroxyl groups that can be found in both rims of calixarene compounds enter into intermolecular hydrogen interactions. Complex4 is potentially more stable with hydrogen bond interactions [53] [54] [55] . Also, as can be seen from Fig. 3 , the -NH 2 and -OH groups of the favipiravir molecule together play an important role in the interactions in all complexes. These values (in Table 1 ) are significantly higher than the previous reported values. In the literature, adsorption enthalpy values for favipiravir adsorption on Si-doped and Fe-doped fullerenes have been calculated as − 182 kJ/mol and − 149.6 kJ/mol, respectively [56, 57] . However, it is not desirable for the adsorption energy change values to be large, because that much energy must be given for desorption. Looking at the Gibbs free energy change (∆G) values, it has been revealed that adsorption can occur spontaneously for only complex4, since the ∆G value for the complex4 is negative (-2.0 kJ/mol). In addition, the point to be stated about this result; in this spontaneously forming complex4, the host-guest interaction between the functional group and the drug molecule is not in the hydrophobic cavity of the calix [4] arene4 compound, but from outside of the compound. Because in the optimized geometry of the calix [4] arene4 compound, the -OH group of the functional group is located on the outside of the structure. In the adsorption study carried out in the hydrophobic cavity, the positive ∆G value and the small ∆E value support this result.

In order to investigate the sensitivity of the electronic properties of calix [4] arene compounds to favipiravir molecule, it has been used two parameters, such as E g and workfunction (Φ) to see the sensor properties of calix [4] arene structures for favipiravir molecule. Here E g is the gap between the HOMO and LUMO energies. Based on the literature, E g can be a good indicator for calculating the sensitivity of nanosensors has been shown repeatedly [58, 59] . It has been also mentioned there is a following correlation between E g and electrical conductivity (σ) [60, 61] :

where κ is the Boltzmann's constant, A (electrons/m 3 K 3/2 ) is a constant and T is temperature. Numerous papers have shown that the results of using this formula are confirmed by the results of experimental studies [62, 63] . Eq. (10)

demonstrates that the decrease in E g increases the population of conduction electrons exponentially. Therefore, the presence of the chemical in the environment increases the electrical conductivity.

The sensor response factor (R) is defined in following equation [64] to predict the magnitude of the electrical change: Here σ1 and σ2 are the electrical conductivity signals of the calix [4] arene molecule and calix [4] arene-favipiravir complex, respectively. In other words σ1 and σ2 are the electrical conductivity of the structures before and after adsorption, respectively.

R-values were calculated using Eq. (12) . According to the results, it has been revealed that the complexes have a ratio between the response factor and ∆E g values. The sensor response factor was quite high for all complexes. The com-plex4 has the highest R value and this value was calculated to the 1.2 × 10 11 . Moreover, R-values for complex1, com-plex2 and complex3 were computed as 2 × 10 10 , 2.6 × 10 9 and 4.1 × 10 9 , respectively. According to these results, it can be mentioned that the sensitivity of calix [4] arene compounds to the favipiravir drug was very high. If the adsorption of a material changes the work function (Φ) value of the sensor, it affects the gate voltage, gives an electrical signal, and helping chemical recognition [65, 66] . The Φ is assumed to be the amount of energy required to remove an electron from the Fermi level.

Here, E F is Fermi level energy and V el (+ ∞) is the electrostatic potential energy of the electron, located far from the surface of the material and considered to be zero. Supposing V el (+ ∞) = 0, Φ equals to -E F . Then the Fermi level can be computed as follows: Table 2 shows the electronic properties of calix [4] arene molecules, including HOMO, LUMO, E g , Fermi level and workfunction (Φ) change well from favipiravir drug adsorption. Considering the these calculated values, it has been determined that there was a serious decrease in the E g values of the calix [4] arene compounds in the study. This means that calix [4] arene compounds can be good candidates for sensing the favipiravir molecule. It is also stated in the table that the workfunctions (Φ) of these sensor candidates have increased by about 20 percent.

Chemical-hardness (η), chemical-potential (µ), electronegativity (χ) and electrophilicity (ω) values calculated according to HOMO and LUMO values are listed in Table 3 . According to the results, host molecules have become more soft structures after adsorption. Electronegativity of all calix [4] arene molecules increased with significantly increasing their chemical potential and electophilicity. Moreover, Natural Bond Orbital analysis (NBO) was used in this study to obtain NBO charge distributions before and after favipiravir molecule adsorption onto calix [4] arene structutes. The total charge of favipiravir

molecule after the adsorption was calculated as − 0.004e, − 0.056e, − 0.048e and − 0.053e on complex1, complex2, complex3 and complex4, respectively. According to these results, it has been mentioned that charge transfer has occurred from calix [4] arene compounds to the drug molecule (favipiravir) in all complexes. Figure 4 represents the HOMO and LUMO illustrations of calix [4] arene structures and favipiravir molecule adsorbed calix [4] arene structures (namely complexes). According to the HOMO and LUMO analysis (Fig. 4) , generally HOMOs are located in the electron-donating part (calix [4] arenes) while LUMOs are located in the electronreceiving part (favipiravir). It should be noted that the extremely strong interactions do not detect the molecules as they demonstrate the trouble in desorbing the adsorbate and this system is subject to longer recovery times. The traditional transition theory predicts a much longer recovery time if the adsorption energy increases significantly. The following equation can be used to explain this situation [61, 63] . Here the recovery time is τ, energy of adsorption is E ad , temperature of adsorption is T, k is the constant of Boltzmann (~ 8.368 × 10 -3 kJ/mol) and the attempt frequency (ν 0 ) is commonly assumed to be a typical value ~ 10 12 s −1 [67, 68] . This equation shows that recovery times increase exponentially with more negative adsorption energy (E ad ) values. The favipiravir molecule's adsorption energy is not too high to prevent the recovery of the calix [4] arene1, calix [4] arene2, calix [4] arene3 and calix [4] arene4 depending on the equation stated. The recovery times were calculated in the range of 1.14 × 10 -5 s-6.8 × 10 -10 s.

The density of states (DOS) of the host structures and the host-guest complex structures were presented in Fig. 5 . As shown in this figure, the distance between DOS plots were shifted by the reduction of the E g of calix [4] arene structures. This is in good agreement with the charge transfer between the guest molecule and the host molecules. The DOS analysis confirms the calix [4] arene structures band gap reduction, which means that the calix [4] arene molecules' electrical Figure 6 gives the distribution of electrostatic potential (ESP) for calix [4] arene structures and favipiravir adsorbed calix [4] arene complexes. The positive and negative areas of the Van der Waals surface described blue and red colors, respectively, on the ESP maps [69, 70] . The electrostatic potential decreases by different colors in order to blue-green-yellow-red. According to the ESP distribution analysis, it is seen that the blue colors increase after the complex formation. This indicates that the electrostatic potential increases between host and guest molecules).

The vibrational frequency values of favipiravir molecule and complexes are given in the Table 4 . The adsorption behavior of the favipiravir molecule on calix [4] arene compounds was investigated by taking into account the changes in the most important peaks in the infrared spectra of favipiravir. When the stretching frequencies of the favipiravir molecule and 4 complexes are examined, the frequencies of the C=O, NH 2 and O-H groups of favipiravir draw attention. The vibrational frequencies of the important functional groups of the favipiravir molecule calculated in the theoretical studies previously reported are approximately ν C=O:1700, ν symmetrical N-H:3450, ν asymmetrical N-H:3600 [71] and ν C-F:1320, ν C=O:1810, ν s N-H:3450, ν N-H:3650 (cm −1 ) [57] . These values are comparable with the calculated frequency values. In this study, IR frequency values were calculated for optimized calix [4] arene compounds and the characteristic vibration peaks obtained are: calix [4] arene1; ν O-H:3204 (cm −1 ), calix [4] arene2; ν O-H:3208 (cm −1 ), calix [4] [72] , 3160 [73] , ν S-H: 2564 [74] , ν C=O: 1720 [75] , 1681 [76] (cm −1 ). After adsorption, O-H and NH 2 frequencies of favipiravir were redshifted according to free favipiravir (See Fig. 7) . Especially in complex4, the significant decrease in O-H frequency explains the high adsorption energy. In addition, in O-H frequency shifts of calix [4] arene1, calix [4] arene2, calix [4] arene3 compounds and in O-H and C=O frequency shifts of calix [4] arene4 compound support the high adsorption energy values in the complexes.

In this study, the adsorption processes were carried out in gas phase. In order to investigate the effect of solvent on the adsorption of favipiravir on calix [4] arenes, calculations have been made again. For this purpose the Polarizable Continuum Model (PCM) was utilized for the calculations. Therefore, the effect of solvent was investigated for complex4 because it has the lowest adsorption energy in the gas phase. When water was used as solvent, there was little reduction in the adsorption of the favipiravir molecule on calix [4] arene4 and the ΔE solvent (adsorption in solvent) becomes less negative (− 39.3 kJ/mol). ΔE sol-gas is difference between ΔEs of complex4 in the solvent and gas phase. The ΔE sol-gas for complex4 has been calculated from the following equation [77] : This result is consistent with a previously published study in literature [78] . Consequently, use of water as a solvent has little affected the adsorption of favipiravir on calix [4] arene4. Additionally, one can mention that inclusion of favipiravir in calix [4] arene cavity may involves partial dehydration of the cavity upon entrance of a perhaps already hydrated favipiravir.

The theoretical results of this study show that calixarene compounds that can be derivatized with different functional groups can adsorb and detect favipiravir and similar drug molecules. In particular, using a wide variety of derivatives of these hosts could help studies in this area, where it can improve the adsorption and detection of drug molecules.

It is important to investigate nanomaterials that can be both the carrier and the detector of the favipiravir drug, which is widely used in the treatment processes against the recently emerging COVID-19 disease. In this study, the adsorption and sensor properties of calix [4] arene compounds toward favipiravir antiviral drug were investigated using the DFT method. It has been resulted in that the calix [4] arene compounds are good adsorbents against the favipiravir molecule. In addition, Gibbs free energy change for the adsorption of favipiravir molecule on calix [4] arene 4 structure was only determined as negative value. Thus, it has been seen that the derivatizability of calixarene structures leads to better results. Also, the IR study supports the high adsorption energy values of favipiravir on calixarene. Another focus is the alteration of electrical conductivity in host-guest complex formations. It has been seen that reducing the energy gaps of HOMO-LUMO of all calix [4] arenes increase their electrical conductivity, so all calix [4] arene compounds can be utilized as nanosensor for favipiravir detection. Besides, it was determined that charge transfer took place between calix [4] arene compounds and favipiravir molecule in all complexes. Furthermore, the calculations with solvent identified that the drug molecule weakly interacts with the calix [4] arene compound and the adsorption energy becomes slightly less negative value. Considering these results, the calixarene derivatives give good results in sensing or adsorption of favipiravir drug at room temperature. As a conclusion, calix [4] arene structures used in this study might be utilized as both electronic sensor and workfunction sensor for favipiravir molecule detection.

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Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health

The numerical-calculations reported in this paper were partially performed at TUBITAK-ULAKBIM, High-Performance and Grid-Computing-Center-(TRUBA resources).

The authors declare that they have no conflict interests.