Molecular Mobility of Different Forms of Ketoprofen Based on DFT Calculation Data ^†

Abstract

Ketoprofen is a representative of the group of non-steroidal anti-inflammatory drugs widely used in modern medical therapy. The intramolecular dynamics of ketoprofen are of particular importance, since the mobility of its main structural fragments is one of the key factors determining the efficiency of drug binding to the enzyme. Investigations of such processes taking into account the acid–base properties of ketoprofen have not been carried out. DFT calculations for molecular, anionic and ion pair forms of ketoprofen were performed at the BP86/def2-TZVP level of theory using ORCA software. The intramolecular dynamics of the main structural fragments were investigated for the molecular, anionic and ion pair forms of ketoprofen. The most stable conformers were revealed for all considered forms, and the barriers of intramolecular rotation were estimated. It was shown that the structures of the ketoprofen forms studied are labile but characterized by different mobility.

1. Introduction

Ketoprofen (2-(3-benzoylphenyl)propionic acid) is a representative of the group of non-steroidal anti-inflammatory drugs (NSAIDs) widely used in modern medical therapy due to their anti-inflammatory, antipyretic and analgesic activity [1,2]. In modern research practice, ketoprofen is often used as a model compound to study the influence of various factors on its biological properties and to develop new methodologies for the identification of compounds of this class by various methods [1,2,3,4,5]. The determination of the detailed mechanism of action of ketoprofen requires studying the structure and dynamics of this molecule, including the configuration, charges and mobility of fragments. In this case, the intramolecular dynamics of ketoprofen are of particular importance, since the mobility of its main structural fragments is one of the key factors determining the efficiency of drug binding to the enzyme [6]. Investigations of such processes taking into account the acid–base properties of ketoprofen have not been carried out. Therefore, an analysis of the intramolecular dynamics of ketoprofen, considering its possible forms, molecular, anionic and ion pair (Figure 1), is of current interest. And the question of how a change in the electronic environment affects the structure, dynamics and properties of ketoprofen is still a matter of discussion.

In this paper, we present the results of the DFT investigation of the intramolecular dynamics of the main structural fragments of ketoprofen (Keto) in molecular and anion forms. Contact ion pairs of a ketoprofen anion with a sodium cation are also considered a small cluster model of sodium ketoprofen (KetoNa).

2. Methods

All DFT calculations were performed using the ORCA 5.0.3 software package [7]. The molecular geometry optimization of the molecular, anionic and ion pair forms of Keto, followed by vibrational frequency calculations and conformational analysis were carried out at the BP86/def2-TZVP level of theory using the approximation of an isolated molecule. The equilibrium configurations of stable conformers were applied for a joint analysis of experimental and calculated data. Only S-enantiomers were considered in calculations for all Keto forms as they are responsible for Keto bioactivity in vivo [8]. The visualization of the stable conformer geometries and the obtained IR spectra of the Keto forms considered was performed with Chemcraft 1.8 software [9]. Spectral convolution was performed with Gaussian functions having a full width at half-maximum of 10 cm⁻¹ and by setting the intensity at the band maximum equal to the calculated absolute infrared intensity.

The ketoprofen and sodium ketoprofen samples used in experimental investigations were from the NERA group (FLNP, JINR) collection. All compounds were spectroscopy-grade and used without additional purification.

The experimental infrared spectra of Keto and its sodium salt were recorded at room temperature using a Nicolet iS50 IR Fourier spectrometer (Thermo Fisher Scientific, Waltham, MA, USA) with a built-in ATR accessory. The spectral range was 4000–400 cm⁻¹.

3. Results and Discussion

A study of the intramolecular dynamics of the main structural fragments was conducted for the molecular, anionic and ion pair forms of Keto at the onset. In the structure of the ketoprofen molecule, three key fragments can be distinguished, consisting of an internal aromatic ring with two substituents—a benzoyl fragment and propionic acid residue. Their relative position determines the spatial configuration of Keto in all of its forms. Thus, torsion angles α (O³-C²-C⁴-C⁶), β (C²-C⁴-C⁶-C⁷) and γ (C⁷-C⁸-C⁹-C¹⁰) (Figure 2) were chosen as the coordinates of internal rotation.

As a result of the intramolecular rotation of the main structural fragments in the molecular, anion and ion pair forms of Keto, the most stable conformers were revealed for all the considered forms. Also, the barriers of intramolecular rotation were estimated. It was shown that the structures of the Keto forms studied are labile but characterized by different mobility (Figure 3). For all forms of Keto, the benzoyl fragment is characterized by the lowest mobility (estimated barriers are within 9–32 kJ/mol). The least labile is the anionic form of Keto (estimated barriers are within 11–32 kJ/mol). The dissociation of Keto leads to a decrease in the mobility of its structural fragments, and the formation of contact ion pairs reduces this effect. The structures of the most stable conformers for the considered forms of Keto are presented in Figure 4. Some key parameters of the molecular geometry and electron structure of them are listed in

Table 1. Some key parameters of the molecular geometry and electron structure of the most stable conformers for the Keto forms considered. Atom numbering corresponds to that in Figure 2.

Parameters	Molecular	Anion	Ion Pair
C2-O3, Å	1.215	1.260	1.274
C2-O1, Å	1.365	1.250	1.276
C2-C4, Å	1.526	1.632	1.547
C4-H4a, Å	1.100	1.104	1.099
C4-C6, Å	1.536	1.526	1.537
C4-C5, Å	1.528	1.498	1.522
O3-C2-O1, °	122.59	130.34	124.31
O3-C2-C4, °	125.88	114.28	117.52
α (O3-C2-C4-C6), °	92.2	−54.3	−96.3
β (C2-C4-C6-C7), °	122.8	70.2	116.8
γ (C7-C8-C9-C10), °	−32.3	−27.3	−29.8
μ, D	3.07	7.22	9.19
EHOMO, eV	−5.84	−1.02	−5.43
ELUMO, eV	−2.93	0.06	−2.53
ΔE (LUMO-HOMO), eV	2.91	1.08	2.90
Q (O1), e	−0.343	−0.421	−0.543
Q (O3), e	−0.286	−0.454	−0.524
Δq (O1-O3), e	0.057	0.033	0.019

.

For the purpose of comparative analysis, the experimental FTIR-ATR spectra of the Keto and KetoNa samples were measured (Figure 5a). The spectra are in good agreement with the previously obtained data for these compounds [10,11]. For the most stable conformers of Keto in all forms considered, IR spectra were obtained and visualized (Figure 5b). A joint analysis of the molecular modeling results and experimental data on vibrational frequencies for Keto and sodium ketoprofen was performed. Good agreement was obtained between the experimental and DFT-calculated vibrational frequencies of the objects under study (Equations (1)–(3)). It should be noted that in the correlation (Equation (1)) for Keto, the signals of O-H groups were not considered. Since all calculations were performed in the isolated molecule approximation, the value for the O–H stretching obtained corresponded to that for the free hydroxide groups (3592 cm⁻¹), while the experimentally observed values corresponded to the O–H stretching of H-bonded hydroxide groups (3306 cm⁻¹). Moreover, the bands at 2641 cm⁻¹ and 2723 cm⁻¹ in experimental spectra most likely correspond to the O–H stretching in dimers, which can be distinguished in the crystalline structure of Keto [12]. A noticeable difference between the calculated (1743 cm⁻¹) and experimental (1697 cm⁻¹) frequencies of C=O stretching is also due to the intermolecular H-bonds. Therefore, for a more complete description of the experimental vibrational spectra of Keto, further studies taking into account intermolecular interactions are necessary.

Molecular form: ν_exp = (0.986 ± 0.004) ∗ ν_DFT, R = 0.99953

(1)

Anion form: ν_exp = (0.963 ± 0.011) ∗ ν_DFT, R = 0.99845

(2)

Ion pair form: ν_exp = (0.954 ± 0.007) ∗ ν_DFT, R = 0.99932

(3)

When moving from the molecular form (Keto) to the salt form (KetoNa), the vibrations for the carbonyl group C=O disappear in the spectrum, and those corresponding to the carboxylate anion appear. They correspond to the 1583 cm⁻¹ and 1400 cm⁻¹ bands (antisymmetric and symmetric stretching vibrations, respectively) in the experimental spectrum of KetoNa. The vibrational frequencies obtained for the ion pair form are in better agreement with the experimental IR spectroscopy data for sodium ketoprofen as compared to the anion data (Equations (2) and (3)). Thus, the ion pair form of Keto can be considered a small cluster model of sodium ketoprofen.

4. Conclusions

The quantum chemical modeling of the intramolecular dynamics of the molecular, anionic and ion pair forms of ketoprofen showed that by varying the electronic environment of ketoprofen’s reaction center, it is possible to regulate the mobility of the main structural fragments of ketoprofen, which may contribute to its bioactivity. The correct results for describing the dynamics of its most labile salt form can be obtained using complementary methods of vibrational spectroscopy in combination with a cluster model for quantum chemical calculations. For a more complete description of the experimental vibrational spectra of ketoprofen, further studies taking into account intermolecular interactions are necessary, and conducting them will be the next step of our investigations.