**Abstract**

Density functional theory (DFT) is a quantum mechanical approach used to investigate the electronic structure (principally the ground state) of many-body systems, in particular atoms, molecules, and the condensed phases. In this work, we have used DFT/B3LYP/6-31+G(d) level of theory to get insight into the molecular geometry and thermochemical properties of histamine H2-receptor antagonists. Histamine H2-receptor antagonists or H2 blockers are a group of pharmaceutical ingredients that reduce the amount of acid produced by the cells in the lining of the stomach. The potential H2 blockers include cimetidine, famotidine, nizatidine, and ranitidine. The detailed theoretical investigation on the listed H2 blockers in terms of their thermochemical parameters and global descriptive parameters revealed that, though famotidine is the best among them with highest Gibbs free energy, nizatidine showed higher biological activity with high softness, low hardness, and high electrophilicity index. The theoretical vibrational spectra of these four Histamine H2-receptor antagonists were analyzed and the infrared spectra of nizatidine was compared with the experimental IR spectra, and found to be good agreement with the experimental values. Further, frontier molecular orbitals especially the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) were determined and the activation energy of the selected samples were calculated. In addition to this, the amorphisation technique were employed to enhance the solubility and bio availability of the best biologically active H2 blocker nizatidine using broadband dielectric spectroscopy.

**Keywords:** histamine H2-receptor antagonists, density functional theory, molecular orbitals

### **1. Introduction**

The branch of computational chemistry is identified to be one of the nascent applications of technological growth within chemistry. Within this branch, different algorithms are introduced through incorporating aspects of theoretical chemistry for identifying and predicting chemical properties of compounds. Analyzing the results obtained from computational chemistry it was fascinating to note that

the theoretical results provide information with same quality of the data obtained through conducting experiments. With the required level of availability of variables or data, it helps in describing various unobserved chemical phenomena [1]. Computational chemistry is identified to be one of the major components identified to be included in the process of making new chemical products. The use of this technology provides increased efficiency of the drug introduced through analyzing the nature of the particular receptor site. The role of organic chemists is followed by attempting to synthesize the proposed structure of the chemical components, which is occasionally tested by biochemists. This set of actions is iterated by analyzing experimental results after obtaining feedback on the same. The aspect of the feed back provides suggestions for effectively increasing the quality of molecules.

Various tools used by computational chemistry starting from molecular mechanics to higher quantum mechanical calculations including Hartree Fock method, density functional methods & ab initio calculations. The balls and springs model of molecules is identified to be included within molecular mechanics [2]. The element of quantum mechanics is introduced within the ab initio aspect through treating the same with the Schrödinger Equation [3]. Semi-empirical methods are identified to include Hartree-Fock theory in a more simplified version along with empirical corrections resulting in increased performance [4]. DFT or Density Function Theory uses electron density function irrespective of the wave function. The electron density function is also identified as charge density or just merely electron density. Two of the Hohenberg-Kohn theorems which describe that the ground state property of atom or molecule is identified by its electron density function and the energy produced by trial electron density should be either greater than or equal to its true and valid energy, are the main constituents of density functional theory [5]. The Kohn - Sham approach, on the other hand, is identified to analyze the level of variations made by a system through considering an ideal system that is comprised of non-interacting electrons [3]. Through reducing the energy along with Kohn-Sham orbitals, the Kohn-Sham equations can be derived from the energy equation [6, 7].

Experiment and theory are identified to be the major components for the functioning of science and almost all of its disciplines. Hence, one without the other won't be able to effectively assist in the creation of scientific breakthroughs. A theory without experimental data to support it is regarded as a hypothesis, while experiments without theory will not provide a degree of finiteness to it. In the field of science, the advent of the computational facility is identified to provide increased support for such experimental needs. Focusing on the branch of chemistry, computational chemistry is identified to effectively assist in various experimental chores [1]. The major reason for the success of computational chemistry was the chance provided for skipping over the tedious and hazardous chemical experimentation with the help of computer simulation.

Here in this work structural properties along with the reactivity, energy, vibrational properties and frontier molecular orbitals of histamine H2-receptor antagonists (cimetidine, famotidine, nizatidine and ranitidine), are investigated using Density functional theory [4]. H2 blockers are a group of medicines that reduce the amount of acid produced by the cells in the lining of the stomach and are used to treat duodenal ulcers, gastric ulcers and Zollinger-Ellison disease [8]. They are also called 'histamine H2-receptor antagonists' but are commonly called H2 blockers. The H2 blockers compete with histamine for H2 receptors on the stomach's parietal cells and thereby depress the production of hydrochloric acid. They are rapidly absorbed and will reach peak blood levels in 1 to 3 hours. Acid-suppression lasts several hours thereafter and permits peptic ulcers to heal over a few weeks. It also counteracts the corrosive effects of acid, which refluxes into the esophagus

**133**

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

(food pipe) and causes heartburn. Though histamine H2 blockers inhibit the action of histamine on gastric H2 receptors thereby decreasing gastric acidity, they were considered a breakthrough in the treatment of peptic ulcer disease but it is used as non-NSAID ulcers, and control severe esophagitis. There are four H2 blockers available by prescription: cimetidine, ranitidine, nizatidine and famotidine [9]. But we are unaware about the chemical and biological activities of these H2 blockers and information are less to claim best among the four. This work is an attempt to get an insight to the structural and thermochemical properties and parameters such as Gibbs free energy, enthalpy and entropy, and stability of the four selected H2 blockers and to find out which molecule is comparatively active; chemically as well as biologically. Further we have included the molecular dynamics of the best one among the four H2 blockers to enhance its solubility by amorphosizing the sample by quench cooling technique, though such study is out of focus of this chapter.

The input structures the drugs; cimetidine (PubChem: 3033637); famotidine (PubChem: 2756); nizatidine (PubChem: 5702160); ranitidine (PubChem: 3001055) were taken from the PubChem database [10], which are in sdf (Standard Data File) format and were converted to GJF (Gaussian Job File) input files using the applica-

All the quantum calculations have been performed by density functional theory using a Gaussian 09 software package [12]. The initial geometries chosen for calculation was taken from the PubChem database and optimized with DFT/ B3LYP/6-31 + G(d) level of the theory [6]. The B3LYP is Becke's three-parameter practical hybrid methods that add the exchange and electronic correlation terms in DFT, including the Lee, Yang Parr (LYP) functional. The optimized geometry was used for the calculations of harmonic vibrational frequencies at the DFT/ B3LYP/6-31 + G(d) method, it also helps to ensure the systems to be local minimum number imaginary vibration frequencies. The thermochemical properties [13–15] like, hardness (η), softness (S), chemical potential (μ), electronegativity (χ) and electrophilicity index (ω), were calculated using Koopman's theorem for closedshell compounds. Electrostatic potential analysis has also been made to identify the mapping surface of drugs. The thermo chemical properties of the selected molecules were calculated from electronic energy, the equilibrium geometry and

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

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

**2. Materials and method**

**2.1 Materials**

tion Open Babel [11].

**2.2 Computational methodology**

the vibrational frequencies.

**3. Results and discussion**

were depicted in **Figure 1** [16–18].

**3.1 Molecular geometry**

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

(food pipe) and causes heartburn. Though histamine H2 blockers inhibit the action of histamine on gastric H2 receptors thereby decreasing gastric acidity, they were considered a breakthrough in the treatment of peptic ulcer disease but it is used as non-NSAID ulcers, and control severe esophagitis. There are four H2 blockers available by prescription: cimetidine, ranitidine, nizatidine and famotidine [9]. But we are unaware about the chemical and biological activities of these H2 blockers and information are less to claim best among the four. This work is an attempt to get an insight to the structural and thermochemical properties and parameters such as Gibbs free energy, enthalpy and entropy, and stability of the four selected H2 blockers and to find out which molecule is comparatively active; chemically as well as biologically. Further we have included the molecular dynamics of the best one among the four H2 blockers to enhance its solubility by amorphosizing the sample by quench cooling technique, though such study is out of focus of this chapter.
