Research Article | Open Access
FT-IR, Laser-Raman, UV-Vis, and NMR Spectroscopic Studies of Antidiabetic Molecule Nateglinide
The quantum chemical calculations and spectroscopic and theoretical characterizations of nateglinide molecule, a derivative of meglitinide and an oral antidiabetic drug, were performed using FT-IR, Laser-Raman, and NMR chemical shift and UV-Vis analysis methods. The other parameters including geometric structures, optimized geometry, vibrational frequencies, dipole moments, infrared and Raman intensities, and HOMO and LUMO energies of nateglinide molecules were studied using the density functional theory. In addition, the 13C and 1H NMRs were calculated using Gaussian 09 program with the DFT/B3LYP method at the 6-31G + (d, p) basis set. TD-DFT calculations were performed to examine the electronic transitions including orbital energies, absorption wavelengths, oscillator strengths, and excitation energies in methanol. The research was performed to provide detailed spectroscopic information of antidiabetic nateglinide molecule’s monomer conformations.
Meglitinides (glitinides) are insulin secretagogues, and they stimulate insulin release from pancreas [1–3]. Nateglinide, a derivative of meglitinide, is an oral antidiabetic drug used for the treatment of type II diabetes mellitus. Nateglinide lowers the blood glucose levels by stimulating insulin secretion from the pancreas. The structure name of nateglinide is (−)-N-[(trans-4-isopropylcyclohexane) carbonyl]-D-phenylalanine [4–7]. The chemical formula of nateglinide used in the present study is C19H27NO3. The CAS and MDL numbers are 105816-04-4 and MFCD00875706, respectively. The molecular weight of nateglinide is 317.42 g/mol. The synonyms of nateglinide are given as Fastic, N-[(trans-4-isopropylcyclohexyl)carbonyl]-D-phenylalanine, Starlix, and Starsis in .
Jain et al. carried out a work on spectrophotometric determination of nateglinide in bulk and tablet dosage forms . Babu et al. investigated nateglinide with visible spectrophotometry and spectrophotometric methods [10, 11]. Bruni et al. developed a method for the quantification of the polymorphic purity of nateglinide in mixtures formed by polymorphs H and B . Guardado-Mendoza et al. explained that nateglinide and repaglinide are effective in reducing postprandial glucose excursion and HbA1c levels from 0.8% to 1% in T2DM . Rani et al. described two spectrophotometric methods for the determination of nateglinide . Goyal et al. determined the crystal structure and crystallographic parameters of experimentally crystallized polymorphs of nateglinide. Crystallographic parameters of nateglinide polymorphs were given as Form H, Form B, Form MS, and Form S (space groups are P-1, C2, P-4, and P-42C), and the forms were found to exist in triclinic, monoclinic, tetragonal, and tetragonal, correspondingly . Remko  used the methods of theoretical chemistry to elucidate the molecular properties of the hypoglycemic sulfonylureas and glinides (acetohexamide, tolazamide, tolbutamide, chlorpropamide, gliclazide, glimepiride, glipizide, glibenclamide, nateglinide, and repaglinide) which are known as antidiabetic molecules. The geometry and energy of these drugs were computed using the Becke3LYP/6-31G + (d, p) method. Karakaya et al.  investigated the vibrational and structural properties of tolazamide molecule. Ozdemir and Gokce studied the glimepiride molecule as a sulfonylurea compound using FT-IR, Raman and NMR spectroscopy, and DFT theory .
Few studies have been encountered on investigation of nateglinide molecule, which is effectively used against diabetes mellitus. In this regard, the present research was carried out to perform a detailed theoretical and experimental investigation of nateglinide, which is the active ingredient of an antidiabetic drug commonly prescribed as Starlix, using spectroscopic analyses such as FT-IR, Laser-Raman, UV-Vis, and NMR. In the present study, density functional theory study was theoretically performed to obtain the vibrational wavenumbers, FT-IR, Laser-Raman, and NMR chemical shifts and UV-Vis of nateglinide molecule. The recorded experimental data were supported with the computed parameters using theoretical methods at DFT/B3LYP/6-31G + (d, p) level. The obtained theoretical and experimental results were used to give detailed information of the molecular electronic structure of nateglinide.
2. Experimental and Computational Procedures
Nateglinide was purchased from Sigma-Aldrich Corporation in powder form. The melting point of nateglinide is in the range of 137°C–141°C. The chemical name of nateglinide (NTG) is N-(trans-4-isopropylcyclohexyl carbonyl)-D-phenylalanine. This molecule is almost insoluble in water, and highly soluble in methylene and methanol chloride. It shows polymorphism . The optimized monomer structures of antidiabetic molecule are given in Figure 1. The FT-IR spectrum of nateglinide molecule was recorded within 400–4000 cm−1 region at room temperature, using the potassium bromide (KBr) pellet, on a Fourier-transform infrared spectrometer in the solid phase of the sample as shown in Figure 2. The Laser-Raman spectrum was recorded at room temperature in 100–4000 cm−1 region as shown in Figure 3. The 1H and 13C NMR chemical shift spectra of the compound solved in dimethyl sulfoxide (DMSO-d6) were recorded with TMS as the internal standard using the Premium Compact NMR device at 600 MHz frequency and 14.1 Tesla field power. The chemical shifts were reported at ppm level as given in Figures 4 and 5. The ultraviolet visible spectrum of nateglinide dissolved in methanol was recorded using a UV-Vis spectrophotometer in 200–400 nm range at room temperature as given in Figure 6.
B3LYP (Becke, three-parameter, Lee–Yang–Parr) level with 6-31G + (d, p) basis set was used to compute the electronic structure properties of nateglinide molecule [20, 21]. Vibrational wavenumbers, geometric parameters, and molecular properties were calculated using Gaussian 09W software and GaussView5 molecular visualization program on a computer system [22–24]. Veda 4 program was used to compute the potential energy distribution of vibrational wavenumbers as given in Table 1 . The major contributions for the computed electronic wavelengths were obtained by GaussSum 3.0 program as listed in Table 2 .
s, symmetric; as, asymmetric; ν, stretching; δ, in-plane bending; τ, torsion; γ, out-of-plane bending; ds, scissoring and symmetric bending; ρ, rocking; t, twisting; , wagging; IIR, IR intensity (km/mol); SRaman, Raman scattering activity; PED, potential energy distribution; W, wavenumber (cm−1); T, transmittance (%). R2=0.9981 for Monomer 1 and R2=0.9980 for Monomer 2 for IR wavenumbers.
3. Results and Discussion
3.1. Geometric Structure
The experimental data explain the crystallographic structure of nateglinide , and these findings were compared with the calculated results as given in Table 3. The other geometric parameters such as bond lengths, bond angles, and torsion angles with the corresponding literature information are given in Table 3. Zero-point, relative energy values, and dipole moments are given in Table 4. Tessler and Goldberg investigated bis(nateglinide) hydronium chloride, in addition to its self-assembly into extended polymeric arrays with O-H⋯O, N-H⋯Cl, and O-H⋯Cl hydrogen bonds. The title compound contains four dissimilar moieties which are conformationally different in the asymmetric unit .
 L. Tessler, I. Goldberg., bis(nateglinide) hydronium chloride, and its unique self-assembly into extended polymeric arrays via O-H⋯O, N-H⋯Cl, and O-H⋯Cl hydrogen bonds. Acta Cryst. C61 (2005) 738–740.
The C-C bond lengths of the title molecule were calculated at the interval of 1.395–1.558 Å, while they were recorded between 1.352 and 1.543 Å in the literature . The C-N bond lengths of the title molecule were calculated at 1.447 Å and 1.372 Å, while they were recorded at 1.460 Å and 1.332 in the literature . In this research, the C-H bond lengths of the title molecule were calculated at the interval of 1.086–1.103 Å. The calculated C11-C13, C13-C15, C9-C11, C7-C9, C7-C17, C15-C17, C17-C18, C18-C21, C21-C23, C24-C25, C25-C38, C35-C38, C33-C35, C33-C30, C27-C30, C25-C27, C33-C41, C41-C47, and C41-C43 bond lengths for nateglinide are 1.398 Å, 1.395 Å, 1.396 Å, 1.398 Å, 1.401 Å, 1.403 Å, 1.514 Å, 1.558 Å, 1.525 Å, 1.530 Å, 1.546 Å, 1.537 Å, 1.542 Å, 1.542 Å, 1.539 Å, 1.539 Å, 1.554 Å, 1.539 Å, and 1.539 Å, respectively. The calculated bond angles of C24-C25-C27, C24-C25-C38, C25-C27-C30, C25-C38-C35, C38-C35-C33, C35-C33-C30, and C33-C30-C27 are 117.171°, 109.582°, 110.933°, 111.408°, 112.186°, 109.752°, and 112.163°, respectively, in this study. The calculated dihedral angle of C9-C7-C17-C18 is −179.489°.
Jain et al. studied the monomers, dimers, and tetramers of nateglinide to understand the conformational properties. Nateglinide molecule contains two strong hydrogen bond donors as N–H/O–H and two strong acceptors as 2 × C = O . As in the present research, two conformations come into prominence, namely, N-A and N-C. These two differ from others by the relative position of hydrogen in the carboxylic group and by torsional angle across C2–C3–N4–C5 (−169.17° in N-A and −118.57° in N-C). Likewise, the torsional angles of Monomer 1 and Monomer 2 were calculated −169.15007° and −120.87747°, respectively, in the present research.
3.2. Vibrational Frequency Analyses
In the following discussion, nateglinide is experimentally examined using FT-IR, Laser-Raman, UV-Vis spectroscopy, and NMR. The observed and calculated vibrational frequencies, observed and calculated FT-IR intensities, Raman scattering activities, and vibrational assignments of the title molecule are given in Table 1. Nateglinide consists of 50 atoms, and accordingly, it has 144 modes of vibrations according to the relation 3N-6 (for N = 50). In the present research, C-H, C-O, O-H, N-H, and C-C vibrations were examined. As shown in Figures 2 and 3 and Table 1, the experimental and calculated vibrational wavenumbers are in good agreement.
The computations of harmonic wavenumbers, IR intensities, and Raman activities were performed with the DFT/B3LYP/6-31G + (d, p) level. Scaling factors were used for theoretical vibrational wavenumbers. The computed vibrational wavenumbers were scaled as 0.964 for frequencies at the B3LYP/6-31G + (d, p) basis set . The experimental and simulated IR and Raman spectra of the title compound are given in Figures 2 and 3, respectively.
The characteristic bond of nateglinide was observed at 1647 cm−1 with–C=O functional group, 1715 cm−1 with –COOH functional group, 2859–3064 cm−1 with –CH2 functional group, and 3308 cm−1 with –NH functional group . The C=O peak was observed at 1650 cm−1 with an intensity of 333.887 D (10–40 esu2·cm2) . The C=O stretching vibration of nateglinide was observed at 1711 (IR), 1647 (IR)−1647 (R) cm−1, and 1339 (IR)–1339 (R), and the computed scaled wavenumber values for this band were obtained at 1746 cm−1, 1671 cm−1, and 1341 cm−1.
NH stretching peaks appear at 3585.48 cm−1 and 3710.51 cm−1 . In the present case, NH stretching modes are calculated at 3508 cm−1.
The peaks at 2921.26 cm−1–3147.88 cm−1 range have the highest intensity of 122.03 D (10−40 esu2·cm2) due to C-H (aromatic) single stretching and OH sharp peak for the infrared spectrum. There is strong symmetric stretching between carbon and hydrogen (νCH) at 2800–3000 cm−1 frequency range for the Raman spectrum . The C-H aromatic stretching vibration and C-H aliphatic stretching vibrations are at 3074 cm−1, 2933 cm−1, and 2860.88 cm−1 . The C-H stretching bands in molecule were observed at 3289, 3063 cm−1, 3029 cm−1, 2925 cm−1, and 2859 cm−1 in the FT-IR spectrum and at 3285 cm−1, 3063 cm−1, 2937 cm−1, and 2860 cm−1 in the Laser-Raman spectrum. These bands were computed at 3091 cm−1, 3079.98 cm−1, 3071 cm−1, 3062 cm−1, 3057 cm−1, 2934 cm−1, 2922 cm−1, and 2868 cm−1 in our calculations.
The O-H stretching band in the title molecule was computed at 3613 cm−1 in the FT-IR spectrum. The OH in-plane bending vibrations (δHOC) were experimentally obtained at 1290 cm−1 (IR) (cal. with 15% contribution of PED) and 1243(IR)–1243(R) (cal. with 13% contribution of PED) cm−1. The OH in-plane bending vibrations (δHOC) were calculated at 1291 cm−1 (IR) and 1230 cm−1 (IR). The OH out-of-plane bending mode (τHOCC) was observed at 1290 cm−1 (IR) and 1187 cm−1 (IR)–1182 cm−1 (R), whereas it was computed at 1291 cm−1 and 1180 cm−1 with 17% and 13% contribution of PED, respectively.
3.3. 1H and 13C NMR Chemical Shift Analyses
The experimental shielding ranges for 1H NMR and 13C NMR are given as 0–13 ppm and 0–180 ppm, respectively. 1H and 13C NMR chemical shift calculated with gauge-including atomic orbital (GIAO) approach using Gaussian 09 software shows good agreement with the experimental chemical shift. Figures 4 and 5 show the experimental 1H and 13C NMR chemical shift spectra of nateglinide. The experimental 1H and 13C chemical shift values measured in DMSO-d6 solvent and the chemical shift values calculated at the DFT/B3LYP/6-31G + (d, p) level in DMSO solvent are shown in Tables 5 and 6.
R2 = 0.9932 and RMSD = 0.237831578 ppm for Monomer 1 and R2 = 0.9709 and RMSD = 0.403748 ppm for Monomer 2.
R2 = 0.9985 and RMSD = 8.615417071 ppm for Monomer 1 and R2 = 0.9981 and RMSD = 9.136034 ppm for Monomer 2.
1H chemical shift values for Monomer 1 were computed at the intervals of 0.8078–8.1579 ppm in DMSO. 1H chemical shift values for Monomer 2 were computed at the intervals of 0.8144–8.089 ppm in DMSO. The experimental chemical shifts of 1H are measured in the range of 0.69–12.58 ppm. The largest deviation between the calculated and experimental 1H NMR chemical shifts (δexp–δcal.) was obtained for H16 with 0.6135 ppm, whereas the smallest deviation was found for H37 with 0.0009 ppm for Monomer 1. The largest deviation between the calculated and experimental 1H NMR chemical shifts (δexp–δcal.) was obtained for H22 with 1.4 ppm, whereas the smallest deviation was found for H34 with 0.0028 ppm for Monomer 2.
The 13C chemical shifts for Monomer 1 were calculated in the range of 7.0408–163.551 ppm in DMSO ppm, and the 13C chemical shifts for Monomer 2 were calculated in the range of 6.1516–161.592 ppm, while they were experimentally recorded in the range of 20.07–175.54 ppm. The largest deviation between the calculated and experimental 13C NMR chemical shifts (dexp–dcal.) was obtained for C17 with 14.022 ppm, whereas the smallest deviation was found for C33 with 0.6225 ppm for Monomer 1. The largest deviation between the calculated and experimental 13C NMR chemical shifts (dexp–dcal.) was obtained for C23 with 13.948 ppm, whereas the smallest deviation was found for C33 with 0.4279 ppm for Monomer 2.
3.4. UV-Vis Analyses
The obtained and simulated UV-Vis spectrum of nateglinide dissolved in methanol was recorded in the region of 190–350 nm. UV-Vis calculation was performed in methanol using the TD-DFT method with Gaussian 09W software and GaussView5 molecular visualization program. The measured and simulated UV-Vis electronic absorption spectra are given in Figures 6 and 7. Additionally, the experimental and computed electronic absorption wavelengths, electronic transitions, oscillator strengths, excitation energies, and major contributions are listed Table 2. Rajasekaran et al. determined a method in which the absorbance of pure drug and tablet extract in 95% ethanol was measured at 210 nm . Xavier studied the UV detector response of NTG and found the best result at 210 nm . In this research, the wavelength recorded at 212 nm in the experimental UV-Vis spectrum can be assigned to n ⟶ σ∗ transition. The calculated wavelength corresponding to this experimental value was obtained at 216.85 nm with 5.7175 eV value of excitation energy and 0.0120 value of oscillator strength for Monomer 1. The other computed wavelengths are given as 236.51 nm, 228.14 nm, 221.79 nm, 219.16 nm, 216.85 nm, and 207.28 nm. The experimental and computed wavelengths and electronic transitions are in good harmony. The calculated wavelength corresponding to this experimental value was obtained at 212.63 nm with 5.8310 eV value of excitation energy and 0.0133 value of oscillator strength for Monomer 2. The other computed wavelengths are given as 228.64 nm, 219.70 nm, 216.37 nm, 212.63 nm, and 210.78 nm.
3.5. HOMO-LUMO Analyses
The computed molecular energies for Monomer I and Monomer II were obtained as E = −1020.83682668 a.u. and E = −1020.83864468 a.u., respectively. The calculated dipole moments are 5.1216 and 2.3479 debye for Monomer I and Monomer II, respectively. By considering Monomer II, the structural, spectroscopic (IR, Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods. The relative energy between the two monomers is considerably low, and it has a value of −0.99582 kcal/mole. Owing to its more stable structure, dipole moment of monomer 2 is lower than monomer 1. The simulated HOMO and LUMO surfaces, energy values, and their shapes for the title molecule are given in Figure 8. The calculated HOMO and LUMO energy values were computed as −6.9449 eV and −0.8923 eV for Monomer 1 and −6.8336 eV and −0.8101 eV for Monomer 2 at the DFT/B3LYP/6-31G + (d, p) level, respectively.
The structural, spectroscopic (IR, Laser-Raman, NMR, and UV-Vis), and HOMO-LUMO analyses for nateglinide were performed using theoretical computational methods. The computed spectral properties were compared with the experimental data. After the conformational analysis, two molecular geometric forms at the lowest energies were optimized with the DFT/B3LYP/6-31G + (d, p) level. The results can be summarized as follows:(i)The linear correlation coefficient (R2) value between the calculated and experimental  molecular geometric parameters was found as 0.975 for bond lengths (Å) and 0.9605 for bond angles (°), respectively, as given in Table 3.(ii)As a result of the performed analyses, the linear correlation coefficient (R2) values between the experimental and computed vibrational frequencies of Monomer 1 and Monomer 2 for IR wavenumbers were found as R2 = 0.9981 and R2 = 0.9980, respectively.(iii)The R2 and RMSD values between the experimental and computed 1H NMR chemical shifts were found as 0.9932 and 0.24 ppm for Monomer 1 and as 0.9709 and 0.40 ppm for Monomer 2, respectively. The R2 and RMSD values between the experimental and computed 13C NMR chemical shifts were found as 0.9985 and 8.62 ppm for Monomer 1 and as 0.9981 and 9.14 ppm for Monomer 2, respectively.(iv)The major contributions for Monomer 1 were found as H-2->LUMO (67%), H-1->LUMO (12%) H-3->LUMO (6%), H-2->L + 4 (5%), and HOMO->LUMO (2%) for 216.85 nm wavelength. The major contributions for Monomer 2 were found as H-3->LUMO (64%), H-1->LUMO (10%) H-1->L + 2 (6%), HOMO->LUMO (3%), and HOMO->L + 1 (4%) for 212.63 nm wavelength.
The data used to support the findings of this study are available from the corresponding author upon request.
(i) The optimized molecular geometry and molecular parameters of nateglinide molecule were investigated. (ii) Molecular structure of nateglinide molecule was studied using DFT. (iii) The complete assignments were performed on the basis of the PED. (iv) The vibrational wavenumbers (FT-IR and Laser-Raman) and UV-Vis spectroscopy were studied using experimental and theoretical methods. (v) The experimental and computed proton and carbon-13 NMR chemical shifts were determined. (vi) All the results were compared with experimental (FT-IR, FT-Raman, UV-Vis, and NMR) spectra.
Conflicts of Interest
The author declares that there are no conflicts of interest.
This work was supported by Bartin University Research Fund Project under the Project no. 2017-FEN-A-005. The author thanks Cankiri Karatekin University Research Center for NMR, FT-IR, and UV-Vis analysis and Niğde Ömer Halisdemir University Center Research Laboratory for Laser-Raman analysis. The valuable help of Assoc. Prof. Dr. Halil Gökçe, Assoc. Prof. Dr. Halil Oturak, Asst. Prof. Adnan Sağlam, Asst. Prof. Firdevs Banu Özdemir, Pharmaceutist Ali Ünsal Keskiner, and Res. Asst. Mecit Öge is also acknowledged.
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Copyright © 2018 Tuba Özdemir Öge. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.