**3. Results and discussion**

#### **3.1 Molecular geometry**

All four histamine H2 receptor antagonists: cimetidine, famotidine, nizatidine, and ranitidine were optimized using DFT method using B3LYP/6-31 + G(d) level of theory. Optimized geometry parameters of the four samples were listed out in the supplementary material for reference. The optimized structure of four H2 blockers were depicted in **Figure 1** [16–18].

#### **Figure 1.**

*Optimized molecular structures of Histamine H2 receptor antagonist using the B3LYP/6-31 + G (d) basis set. (a) nizatidine, (b) cimetidine, (c) famotidine and (d) ranitidine.*

#### **3.2 Vibrational analysis**

Infrared (IR) spectroscopy refers the analysis of interaction of infrared radiation with a molecule. IR spectra of nizatidine obtained from DFT method using B3LYP/6-31 + G(d) level of theory (in **Figure 2(a)**) is compared with the experimental IR spectra (in **Figure 2(b)**) and their assignments were tabulated in **Table 1**.

From the comparison of IR spectra of nizatidine it is clear that, the computed vibrational results were in good agreement with the experimental spectra. IR spectra of cimetidine, famotidine and ranitidine are also generated using DFT method using B3LYP/6-31 + G(d) level of theory and shown in **Figures 3**–**5.**

The vibration at 3109 cm−1 shows the presence of N-H bond. The C-H band is present at 1741 for bending mode of vibration. The vibration band around 1435 and 1462 cm−1 are due to C-H scissor vibration. The bands due to C-N stretching are appeared at 1300 and 1255 cm−1. The band due to C-C skeleton vibration are appeared at 544 and 508 cm−1.

The band due to asymmetric NH2 stretching vibration appears at 3336 cm−1 in the vibrational spectra of famotidine. The vibration band around 1696 and 1664 cm−1 are due to C=N stretching. The vibration at 1088 cm−1 shows the presence of C-N bond. The N-H band is present at 832 cm−1 for out of plain bending mode of vibration.

Spectral analysis of ranitidine shows a vibration at 3442 cm−1 and it is due to the presence of N-H bond. The C=C band is present at 1660 and 1588 cm−1 for stretching mode of vibration. The band due to NO2 stretching is appeared at 1390 cm−1. The vibration band around 1264 and 1174 cm−1 are due to C-N stretching.

#### **3.3 Thermo-chemical properties**

The reaction parameters of the four Histamine H2-receptor antagonists were calculated and tabulated below in **Table 2**.

**135**

2946

**Figure 2.**

1431

**Table 1.**

*31 + G(d) level of theory.*

1519 1534

1189 1219

982 923

**3.4 Frontier molecular orbital analysis**

*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory*

**Experimental IR DFT IR Assignments**

*Theoretical (DFT generated) IR spectra (a); experimental IR spectra (b) of nizatidine.*

2978 2929 Asymmetric C-H stretching vibration

1455 1401 Asymmetric C-H deformation vibration

1379 1370 Symmetric C-H deformation vibration 1221 1264 C-N stretching vibrations

1130 1138 C-H sym. Deformation vibration 1038 1057 C-N stretching vibration

843 850 C-H out-of-plane deformation vibration 746 769 C-C skeleton vibration (rocking) 701 715 CH3-metal groups due to CH2 rocking vibration

1612 1642 C-H vibration (overtone) 1571 1597 C=C stretching vibration

By calculating reaction parameters of histamine H2 receptor antagonist it was found that famotidine is having high free energy, zero-point energy, enthalpy and low entropy. If the Gibbs free energy is higher the solubility will be higher i.e. famotidine having higher solubility. Nizatidine exhibits higher entropy value with less energy indicating that it has higher degree of freedom to be active. Cimetidine is less potent and having low solubility. If nizatidine get a small perturbation in terms of thermal energy it will be in full mode to be active for its specified task.

*Vibrational analysis of nizatidine by experimental and theoretical obtained from DFT method using B3LYP/6-*

Both the energies of HOMO (Highest Occupied Molecular Orbitals) and LUMO (Lowest Unoccupied Molecular Orbitals) are identified. The chemical reactivity of

*DOI: http://dx.doi.org/10.5772/intechopen.95322*

*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory DOI: http://dx.doi.org/10.5772/intechopen.95322*

**Figure 2.**

*Drug Design - Novel Advances in the Omics Field and Applications*

**134**

**3.2 Vibrational analysis**

*(a) nizatidine, (b) cimetidine, (c) famotidine and (d) ranitidine.*

**Figure 1.**

appeared at 544 and 508 cm−1.

**3.3 Thermo-chemical properties**

calculated and tabulated below in **Table 2**.

Infrared (IR) spectroscopy refers the analysis of interaction of infrared radiation with a molecule. IR spectra of nizatidine obtained from DFT method using B3LYP/6-31 + G(d) level of theory (in **Figure 2(a)**) is compared with the experimental IR spectra (in **Figure 2(b)**) and their assignments were tabulated in **Table 1**. From the comparison of IR spectra of nizatidine it is clear that, the computed vibrational results were in good agreement with the experimental spectra. IR spectra of cimetidine, famotidine and ranitidine are also generated using DFT method

*Optimized molecular structures of Histamine H2 receptor antagonist using the B3LYP/6-31 + G (d) basis set.* 

The vibration at 3109 cm−1 shows the presence of N-H bond. The C-H band is present at 1741 for bending mode of vibration. The vibration band around 1435 and 1462 cm−1 are due to C-H scissor vibration. The bands due to C-N stretching are appeared at 1300 and 1255 cm−1. The band due to C-C skeleton vibration are

The band due to asymmetric NH2 stretching vibration appears at 3336 cm−1 in the vibrational spectra of famotidine. The vibration band around 1696 and 1664 cm−1 are due to C=N stretching. The vibration at 1088 cm−1 shows the presence of C-N bond. The N-H band is present at 832 cm−1 for out of plain bending mode of vibration.

Spectral analysis of ranitidine shows a vibration at 3442 cm−1 and it is due to the presence of N-H bond. The C=C band is present at 1660 and 1588 cm−1 for stretching mode of vibration. The band due to NO2 stretching is appeared at 1390 cm−1. The vibration band around 1264 and 1174 cm−1 are due to C-N stretching.

The reaction parameters of the four Histamine H2-receptor antagonists were

using B3LYP/6-31 + G(d) level of theory and shown in **Figures 3**–**5.**

*Theoretical (DFT generated) IR spectra (a); experimental IR spectra (b) of nizatidine.*


#### **Table 1.**

*Vibrational analysis of nizatidine by experimental and theoretical obtained from DFT method using B3LYP/6- 31 + G(d) level of theory.*

By calculating reaction parameters of histamine H2 receptor antagonist it was found that famotidine is having high free energy, zero-point energy, enthalpy and low entropy. If the Gibbs free energy is higher the solubility will be higher i.e. famotidine having higher solubility. Nizatidine exhibits higher entropy value with less energy indicating that it has higher degree of freedom to be active. Cimetidine is less potent and having low solubility. If nizatidine get a small perturbation in terms of thermal energy it will be in full mode to be active for its specified task.

#### **3.4 Frontier molecular orbital analysis**

Both the energies of HOMO (Highest Occupied Molecular Orbitals) and LUMO (Lowest Unoccupied Molecular Orbitals) are identified. The chemical reactivity of

**Figure 3.** *Theoretical IR spectra of cimetidine using DFT/B3LYP/6-31 + G(d) level of theory.*

**Figure 4.** *Theoretical IR spectra of famotidine DFT/B3LYP/6-31 + G(d) level of theory.*

a particular molecule can be determined from their energy gap and eigen values. In addition to being called the frontier orbitals, both HOMO and LUMO are identified to be effectively included within the study regarding charge transfer complex formation reactions [13]. HOMO is identified to represent the ability to be an electron donor through giving an electron, while LUMO, on the other hand, and focuses on the method of gaining electron through being an electron acceptor [14]. The wave function is identified to describe the process of electron absorption as the transition from the ground state to the next excited state. This process is further understood as the excitation of one electron from the highest occupied molecular orbital to the lowest level of an unoccupied molecular orbital. The element of energy gap within both HOMO and LUMO is identified as the parameter describing molecular transport properties [15]. The aspect of electron conductivity also can be understood through the measure of HOMO – LUMO gap along with molecular stability with a large gap denoting higher stability. Hence, the molecular orbitals of all four selected H2 blockers were generated and visualized using DFT, and these molecular orbitals

**137**

one in green).

**Table 2.**

**Figure 5.**

H2 blockers.

π ∗ to π

transition while cimetidine showed

**3.5 Global descriptive parameters**

tabulated below in **Table 3**.

**Sample Molecular** 

**Mass (amu)**

*The reaction parameters of Histamine H2 receptor antagonist.*

*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory*

were shown in **Figure 6** (the positive phase is represented in red and the negative

Nizatidine 331.114 −4.43 −4.43 177.061 −4.43 Cimetidine 252.116 −2.93 −2.93 151.938 −2.93 Famotidine 337.045 −5.36 −5.36 153.901 −5.36 Ranitidine 314.141 −3.54 −3.54 172.629 −3.54

The HOMO, LUMO energies of the selected samples were calculated and

The global parameters are identified to have a larger role to play within the comparison of the behaviors of different compounds and their level of reactivity. A global descriptive parameter is identified to provide the description of the

The difference between HOMO and LUMO energy levels directly gives the band gap or energy gap of the compound. The higher the energy gap lower will be the reactivity of the molecule. Comparing the orbital energy parameters of histamine H2 receptor antagonist, nizatidine is found to be having lower energy gap, which shows that nizatidine is more chemically reactive than others. At the same time cimetidine has high energy gap indicating its less reactivity. So, we can infer that nizatidine is the most biologically active API while cimetidine is the least among the

π to π∗

∗ transition and

**Gibbs Free Energy (109**

 **kJ/mol)**

transition and ranitidine exhibited a

**Entropy (Cal/mol)**

π to π

The possible transitions exhibited by nizatidine and famotidine is

transition. The least energy required must be for

this may be the reason for high reactivity of nizatidine.

*Theoretical IR spectra of ranitidine DFT/B3LYP/6-31 + G(d) level of theory.*

**Zero point Energy (109**

 **kJ/mol)**

**Enthalpy (109**

 **kJ/mol)**

π to π

*DOI: http://dx.doi.org/10.5772/intechopen.95322*

*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory DOI: http://dx.doi.org/10.5772/intechopen.95322*

#### **Figure 5.**

*Drug Design - Novel Advances in the Omics Field and Applications*

*Theoretical IR spectra of cimetidine using DFT/B3LYP/6-31 + G(d) level of theory.*

*Theoretical IR spectra of famotidine DFT/B3LYP/6-31 + G(d) level of theory.*

a particular molecule can be determined from their energy gap and eigen values. In addition to being called the frontier orbitals, both HOMO and LUMO are identified to be effectively included within the study regarding charge transfer complex formation reactions [13]. HOMO is identified to represent the ability to be an electron donor through giving an electron, while LUMO, on the other hand, and focuses on the method of gaining electron through being an electron acceptor [14]. The wave function is identified to describe the process of electron absorption as the transition from the ground state to the next excited state. This process is further understood as the excitation of one electron from the highest occupied molecular orbital to the lowest level of an unoccupied molecular orbital. The element of energy gap within both HOMO and LUMO is identified as the parameter describing molecular transport properties [15]. The aspect of electron conductivity also can be understood through the measure of HOMO – LUMO gap along with molecular stability with a large gap denoting higher stability. Hence, the molecular orbitals of all four selected H2 blockers were generated and visualized using DFT, and these molecular orbitals

**136**

**Figure 3.**

**Figure 4.**

*Theoretical IR spectra of ranitidine DFT/B3LYP/6-31 + G(d) level of theory.*


#### **Table 2.**

*The reaction parameters of Histamine H2 receptor antagonist.*

were shown in **Figure 6** (the positive phase is represented in red and the negative one in green).

The possible transitions exhibited by nizatidine and famotidine is π to π ∗ transition while cimetidine showed π to π transition and ranitidine exhibited a π ∗ to π transition. The least energy required must be for π to π ∗ transition and this may be the reason for high reactivity of nizatidine.

The HOMO, LUMO energies of the selected samples were calculated and tabulated below in **Table 3**.

The difference between HOMO and LUMO energy levels directly gives the band gap or energy gap of the compound. The higher the energy gap lower will be the reactivity of the molecule. Comparing the orbital energy parameters of histamine H2 receptor antagonist, nizatidine is found to be having lower energy gap, which shows that nizatidine is more chemically reactive than others. At the same time cimetidine has high energy gap indicating its less reactivity. So, we can infer that nizatidine is the most biologically active API while cimetidine is the least among the H2 blockers.

#### **3.5 Global descriptive parameters**

The global parameters are identified to have a larger role to play within the comparison of the behaviors of different compounds and their level of reactivity. A global descriptive parameter is identified to provide the description of the

#### **Figure 6.**

*Molecular orbitals of Histamine H2 receptor antagonist using the B3LYP/6-31 + G (d) basis set. (1) a. HOMO Energy =- 6.209 eV, b. LUMO Energy = - 1.650 eV; (2) a. HOMO Energy = -6.052 eV, b. LUMO Energy = -0.475 eV; (3) a. HOMO Energy =- 5.755 eV, b. LUMO Energy = - 0.957 eV; (4) a. HOMO Energy = -6.114 eV, b. LUMO Energy = -1.439 eV.*

connection between the chemical reactivity of the molecule along with the range of sensitiveness exhibited to the various external conditions. Various aspects such as chemical potential, chemical hardness, electro negativity, electrophilicity, and

**139**

*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory*

**Sample EHOMO (eV) ELUMO (eV)** ∆**E (eV)** Nizatidine −6.209 −1.650 4.559 Cimetidine −6.052 −0.475 5.577 Famotidine −5.755 −0.957 4.798 Ranitidine −6.114 −1.439 4.675

softness are contained within the global descriptive parameters. These quantities correspond to the linear responses of the electron density with respect to the changes in the external potential and number of electrons [13]. The aspect of chemical hardness (η) can be understood as the resistance introduced by elements towards deformation or even polarization of the electron cloud of the element which is introduced through following chemical reactions conducted upon the same. Chemical softness (s), on the contrary to the chemical hardness, is identified to provide a measure of the capacity of the molecule for receiving electrons [14]. Through analyzing this case by considering the aspect of the HOMO – LUMO gap, a hard element is identified to have a larger HOMO – LUMO gap compared to a softer element. As the aspect of electro negativity (χ) describes the ability of the molecule for attracting electrons and reaching equalization much more quickly, it is identified to introduce low reactivity. The tendency for an electron to escape from an equilibrium state is referred to as chemical potential while the strength of

*Orbital energy parameters of studied compounds using DFT/B3LYP/6-31 + G (d) level of theory.*

electrophilies of elements is identified through electrophilicity indices.

The global properties were calculated by using equations [12, 13, 20].

where EHOMO is the energy of HOMO and ELUMO is the energy of LUMO.

( ) <sup>≈</sup> <sup>1</sup> Softness S

Electrophilicity index <sup>2</sup>

were calculated and tabulated below in **Table 4**.

The Global descriptive parameters of the four histamine H2 receptor antagonists

2η

Koopmans' theorem states that in closed-shell Hartree–Fock theory, the first ionization energy of a molecular system is equal to the negative of the orbital energy of the highest occupied molecular orbital (HOMO) i.e., Koopmans' theorem equates the energy of the HOMO with the negative of the ionization potential [19].

( ) ≈ − HOMO Ionization potential IP E (1)

Electron affinity EA E ( ) ≈ − LUMO (2)

( ) *IP EA* <sup>−</sup> Hardness η ≈ 2. (3)

(5)

(7)

( ) *IP EA* <sup>+</sup> Electronegativity χ ≈ <sup>2</sup> (4)

Chemical potential(µ ≈ −χ ) (6)

µ

η

(ω ≈) <sup>2</sup>

*DOI: http://dx.doi.org/10.5772/intechopen.95322*

**Table 3.**


*Studies on Histamine H2-Receptor Antagonists by Using Density Functional Theory DOI: http://dx.doi.org/10.5772/intechopen.95322*

**Table 3.**

*Drug Design - Novel Advances in the Omics Field and Applications*

**138**

**Figure 6.**

*Energy = -6.114 eV, b. LUMO Energy = -1.439 eV.*

connection between the chemical reactivity of the molecule along with the range of sensitiveness exhibited to the various external conditions. Various aspects such as chemical potential, chemical hardness, electro negativity, electrophilicity, and

*(1) a. HOMO Energy =- 6.209 eV, b. LUMO Energy = - 1.650 eV; (2) a. HOMO Energy = -6.052 eV, b. LUMO Energy = -0.475 eV; (3) a. HOMO Energy =- 5.755 eV, b. LUMO Energy = - 0.957 eV; (4) a. HOMO* 

*Molecular orbitals of Histamine H2 receptor antagonist using the B3LYP/6-31 + G (d) basis set.* 

*Orbital energy parameters of studied compounds using DFT/B3LYP/6-31 + G (d) level of theory.*

softness are contained within the global descriptive parameters. These quantities correspond to the linear responses of the electron density with respect to the changes in the external potential and number of electrons [13]. The aspect of chemical hardness (η) can be understood as the resistance introduced by elements towards deformation or even polarization of the electron cloud of the element which is introduced through following chemical reactions conducted upon the same. Chemical softness (s), on the contrary to the chemical hardness, is identified to provide a measure of the capacity of the molecule for receiving electrons [14]. Through analyzing this case by considering the aspect of the HOMO – LUMO gap, a hard element is identified to have a larger HOMO – LUMO gap compared to a softer element. As the aspect of electro negativity (χ) describes the ability of the molecule for attracting electrons and reaching equalization much more quickly, it is identified to introduce low reactivity. The tendency for an electron to escape from an equilibrium state is referred to as chemical potential while the strength of electrophilies of elements is identified through electrophilicity indices.

Koopmans' theorem states that in closed-shell Hartree–Fock theory, the first ionization energy of a molecular system is equal to the negative of the orbital energy of the highest occupied molecular orbital (HOMO) i.e., Koopmans' theorem equates the energy of the HOMO with the negative of the ionization potential [19]. The global properties were calculated by using equations [12, 13, 20].

$$\text{Ionization potential (IP)} \approx -\mathcal{E}\_{\text{HOMO}}\tag{1}$$

$$\text{Electron affinity} \left(\text{EA}\right) \approx -\text{E}\_{\text{LUMO}} \tag{2}$$

where EHOMO is the energy of HOMO and ELUMO is the energy of LUMO.

$$\text{Hardness} \left( \eta \right) \approx \frac{IP - EA}{2} \tag{3}$$

$$\text{Electronegativity} \left( \chi \right) \approx \frac{IP + EA}{2} \tag{4}$$

$$\text{Softness} \left( \mathbf{S} \right) \approx \frac{1}{2\eta} \tag{5}$$

$$\text{Chemical potential} \left( \mu \right) \approx -\chi \tag{6}$$

$$\text{Electropibility index} \left( \text{o} \right) \approx \frac{\mu^2}{2\eta} \tag{7}$$

The Global descriptive parameters of the four histamine H2 receptor antagonists were calculated and tabulated below in **Table 4**.

