Determination of Infrared , Raman , ( 1 H and 13 C )-NMR Spectra and Density of State of Nateglinide Oral Antidiabetic Drug

Diabetes is a deficiency in the body’s capability to transmute excess glucose to glycogen. Two classes of antidiabetic drugs were identified and nateglinide is a sub-division of oral antidiabetic drugs belonging to Meglitinides family. Gaussian 09 code which uses density function theory as working principle was used to study the geometric, infrared, Raman, 1H-NMR, 13C-NMR spectrum and density of state of the nateglinide antidiabetic drug using exchange functional B3LYP/6-311G. For the geometry optimization, it was observed that there is the appearance of a new additional bond between C12 and N4 which changes the natural nature of both 1H-NMR and 13C-NMR spectra. For infrared and Raman spectra, functional groups and polarizability were observed. However, the result of the density of state shows the large band gap of 5.46758eV and most of the orbitals were occupied by lower valence band.


Introduction
Diabetes is an imperfection in the body's ability to metamorphose extra glucose to glycogen.Glucose is the cardinal source of energy to our body.Food digests to form protein, fat or carbohydrate depending on the nature of the food.Carbohydrate (potatoes, rice, corn, fruit, milk etc.) affected blood sugar directly.A diabetic patient can eat carbohydrate in a moderation.Because glucose transferred conformers (N-A & N-C) are of significant importance.The relative position of the hydrogen in the alkanoic acid and the torsional angle (-169.17° in N-A & -118.57° in N-C) across C 2 -C 3 -N 4 -C 5 are the only differences between the two conformers.The presence of an intermolecular hydrogen bond can be seen between the carbonyl oxygen of -COOH group and amidic hydrogen of -CONH 2 (Figure 1) in the optimized geometry (structure) of N-C.This -O-H interaction confers stability to N-C over N-A with an energy of about 1.15kcal/mol lower than N-A.In both gaseous and solvent phases, similar trend was observed in the energy variation of the two conformers at B3LYP/3-21+G(d) level of optimization coupled with energy estimation at B3LYP/6-31+G(d,p) level [14].

Procedure
Gaussian 09 code [15] which use Density functional theory calculation was performed on the molecular structure of the Nateglinide sources from Ligand Expo (www.http://ligandexpo.rcsb.org).Conformational search was performed on the dihedral angles; C 20 -C 18 -C 16 -H 43 , C 16 -C 15 -N 4 -C 12 , and O 3 -C 17 -C 15 -C 14 .The conformer with the lowest energy was chosen and optimized using a different basis set of; 3-21G, 6-31G, and 6-311G.From the highest basis set, frequency calculations were performed.Local minima or saddle point (transition state) were the determinant for the measurement of zero point energy.From the result Infrared, Raman and Density of state spectra ware plotted.However, 1 H and 13 C-NMR calculations on both the structure before and after optimizations were carried out and the result was plotted.

Conformational search
From table 1, it was observed that the conformer C 20 -C 18 -C 16 -H 43 has the lowest energy of -2762.448518eV when compared with others and hence it's the most stable.However, it was discussed in detail [16] shows the result of relative energy against torsion angle rotated through 60 o , and it was found that the lowest energy -415.4805535eV rotate at 240° and transition state of 400.8615826 eV.

Optimize structure
As discussed in the [16] it was discovered that there was increased in the bond between Nitrogen N 4 and carbon C 12 as is a meglitinide past-acting β-cell selective and Potassium Adonosine Triposphate (KATP) blocker for improving glycemic control.Nateglinide is a novel oral glucose regulator.It contains amino-acid that reduce blood sugar level by triggering insulin from the pancreas [5,6].
Nateglinide is directly related to Sulphonylureas (SUR1) and it binds quickly to the SUR1 receptor with low affinity.The prompt link and break makes the drug a unique (Fast-on Fast-off effective).Taking Nateglinide instantly before meal, it will stimulate insulin and provide control for postprandial hyperglycemia.The common action of both Nateglinide and SUR1 are on hypoglycemic such as glibenclamide and glipizide.Clinical comparison on both KATP and peroxisome proliferation active receptor (PPAR) gamma have shown that Nateglinide is more serviceable in attenuating postprandial glucose than any other hypoglycemic.Treatment of diabetics with Nateglinide provide patient with effective improvement for controlling plasma glucose [5].
In this work, the molecular structure of Nateglinide antidiabetic drug was modeled.The conformer with the lowest energy was chosen among the four conformers.Geometry optimization, Infrared, Raman spectrum, Density of state and 1 H & 13 C-NMR were computed.

Conformational Setting of Nateglinide
Basically, drugs are designed in such a way that it is activity result from its binding to the receptor as such protein [7].When ligands bound within the binding moiety, it shows geometric and chemical complementaries [8].In any drug designed studies, a receptor is regarded as a fairly rigid molecule.While a ligand has a number of degree of freedom, dominantly torsional ones around bonds connecting atoms.Any kinematically allowed substitution of the ligand's atoms in 3D spatial orientation defines conformation and this conformation predicts the ligand's internal energy.The lower the energy of conformer the higher the stability [9,10].
The confirmation of a molecule is largely controlled by the number of freely rotatable bond or the degree of freedom (DOF) together with the bond angle, torsional angle and bond length.In reality, only torsional DOFs are regarded because these are the only ones that attain greater variation [7].In a number of pharmaceutical molecules, the numbers of torsional DOFs are between 3 and 15 [11].
The different conformations result from rotation about the single bond, and the energy needed for the rotation is below 10kcal/mol in most cases [12].In nateglinide, there are six available rotatable bonds; they are about  shown in figure 1. Figure 1a shows the initial geometry of the structure with a single bond between N 4 and C 12 .Also, figure 1b shows the appearance of the additional bond between N 4 and C 12 .This was due to the fact that after optimization, the structure was now in the ground state and hence the energy was the lowest -2777.84622eV.

Infrared and Raman spectrum
Infrared and Raman spectra are indispensable apparatus for the lucubration and demonstration of molecular structures (organic or inorganic).Vibes frequencies appear in the dominion of the electromagnetic spectrum at 13333 cm -1 to 50 cm -1 range and beyond are generating a change in the active dipole-moment and vibration of molecules produces polarized electron know as active Raman.
For this paper 144 possible molecular vibration was computed for nonlinear Nateglinide molecule structure using the relation 3N-6 (N= 50).
Figure 2 shows the infrared spectrum of Nateglinide antidiabetic molecule.The spectrum occurs in the frequency region of 4000 cm -1 to 28 cm -1 .It was observed that there mono-substituted benzene peaks at around 750 cm -1 .Also, C=O peak was observed at 1650 cm -1 intensity of 333.887D (10 -40 esu 2 cm 2 ).However, there are peaks at range 2921.26cm -1 to 3147.88 cm -1 with the highest intensity of 122.03 D (10-40 esu 2 cm 2 ) due to C-H (aromatic) single stretching and OH sharp peak.Finally two peaks appear at 3585.48 cm -1 and 37105.1 cm -1 with frequencies at 13.5589 D(10 -40 esu 2 cm 2 ) and 59.32 D(10 -40 esu 2 cm 2 ) respectively these were due to NH (secondary amine) stretching.The two peaks may result from formation and deformation of hydrogen bond between -NH and neighboring C=O.

Density of state
The density of state in a condensed matter gives an account for the possible number of state per interval of energy available occupied.Also, it has been used to widely to study physical properties of matter and essential for determining the carrier concentrations and energy distributions of carriers within the semiconductors.Figure 4 shows the density of state spectrum of Nateglinide antidiabetic drugs.It was observed that between the energy ranges of -20 eV to -15 eV, there is five number of state and highest intensity of 2 eV -1 .Between -15 eV to -5 eV there is ten number of states and highest intensity of 4.5 eV -

1
. This shows that electrons populations are higher at valence band.Also, the energy gap of 5.46758 eV was measured.However, due to the large band gap, the most of the electrons were at higher valence band and hence little electrons were transferred to the lower conduction band.

Nuclear Magnetic Resonance (NMR)
Figure 5 and 6 shows the predicted 1 H-NMR and 13 C-NMR structure of Nateglinide antidiabetic drugs respectively.ChemDraw 12 software was used to predict the 1 H-NMR and 13 C-NMR structure of the original geometry.It was found that the shielding range for 1 H-NMR and 13 C-NMR were 0 to 12 ppm and 0 to 180 ppm respectively.Also for 1 H-NMR there were more H n at upfield at about 4 ppm and little at downfield.A similar trend was observed for 13 C-NMR with more C n below 60 ppm (upfield) and little at downfield.Figure 8 shows the 13 C-NMR.It was found that C 17 is the most shielded carbon atom despite been doubly bonded to oxygen in one way and single bonded to another oxygen atom in another way thought to be downfield but upfield this largely attributed to C 12 -N 4 junction.In fact, all the unusualities of these NMR spectra both 1 H, 13 C, 14 N, and 16

Conclusion
Nateglinide is belonging to the family of Meglitinides and special antidiabetic drugs for diabetics (type 2).Its effect on the diabetic disease was emphases and the need to improve its chemical manufacturing was also highlighted.Conformational search was performed on the different dihedral angles on the molecular structure.The structure with the lowest conformer was chosen and optimized under different basis sets.The ground state energy of the highest basis set was found to be -2777.84622eV.However, infrared spectra (IR-spect), Raman spectra (R-spect), Density of State spectrum (DOS) and Nuclear Magnetic Resonance spectra (NMR) studies on the structure were reported.
C 1 -C 2 , C 2 -C 3 , C 3 -N 4 , C 5 -C 6 , C 7 -C 8 and C 3 -C 9 bonds [13].B3LYP optimization of the four reported conformers (N-A, N-B, N-C & N-D) shows that N-A and N-B vary only in -O-C 5 -C 6 -H torsional angle.The torsional angle of N-A and N-B is across a common rotatable bond thus regarded as same.N-C and N-D conformers appeared to be similar at the end of the optimization.Therefore, only two

Figure 1a and 1b :
Figure 1a and 1b: Optimized structure of Nateglinide antidiabetic drug obtained: (a) Before Optimization (b) After Optimization.

Figure 7 shows the 1
Figure7shows the 1 H-NMR, and it was observed that H 45 , H 46 , H 48 , H 49 , and H 50 : are aromatic protons spread over the range 25.39 to 25.86 ppm relative to the rest protons; this indicates that they are relatively equivalent magnetically as they are all within 0.47 ppm.H 47 : shielded up field less than aromatic/ benzene protons high than other protons.H 42 : deshielded down Figure8shows the13 C-NMR.It was found that C 17 is the most shielded carbon atom despite been doubly bonded to oxygen in one way and single bonded to another oxygen atom in another way thought to be downfield but upfield this largely attributed to C 12 -N 4 junction.In fact, all the unusualities of these NMR spectra both 1 H,13 C,14 N, and16 O obeys the dividend of C 12 -N 4 junction.C 12 also shielded relatively to the other C-atoms except for C 17 .Also, C 18 is the most shielded of all the benzene carbon for being the closest to the C 12 -N 4 junction.For C 22 , C 19 , C 20 , C 21 , and C 22 are the remaining carbon atoms of the aromatic ring which showed signal between 54.24 to 56.34 ppm and are relatively upfield and have a relatively similar magnetic effect on the applied field.For C 15 , C 8 , C 5 , C 16 , and C 11 : the absorption peaks of these carbons appeared in the range 131.36 to 148.82 downfield.C 7 , C 6 , C 9 , and C 10 : are downfield carbons of cyclohexane moiety, the other two carbons (C 5 &C 8 ) are upfield relative to the aforementioned ones.Lastly, C 13 and C 14 are carbons showed closed similarity in a magnetic field and hence absorbed in closed δ-value and were the most desheilded carbon atoms of the molecule.
H-NMR, and it was observed that H 45 , H 46 , H 48 , H 49 , and H 50 : are aromatic protons spread over the range 25.39 to 25.86 ppm relative to the rest protons; this indicates that they are relatively equivalent magnetically as they are all within 0.47 ppm.H 47 : shielded up field less than aromatic/ benzene protons high than other protons.H 42 : deshielded down to around 27.87 ppm for being attached to the carbon atom directly bonded to nitrogen.H 41 : deshielded down further to 28.25 ppm for been directly attached to nitrogen which can directly conjugate with neighboring carbonyl group.H 43 and H 44 : methane hydrogens spread over 29.19 to 30.44 ppm and are directly connected to the carbon atom neighboring aromatic ring and hence deshielded.H 28 , H 25 , H 33 , H 32 , H 30 , H 29 , H 35 , H 40 , H 31 and H 34 : they are deshielded to a range 30.73 to 31.52 ppm (i.e., they are all spread within 0.89 ppm) they have almost the same magnetic effect.