THERMODYNAMIC INVESTIGATION OF PROMETHAZINE, LORATADINE, CETIRIZINE AND BUCLIZINE AS ANTIHISTAMINE DRUGS; MONTE CARLO AND SEMI-EMPIRICAL STUDIES INVESTIGACIÓN TERMODINÁMICA DE PROMETAZINA, LORATADINA, CETIRIZINA Y BUCLIZINA COMO MEDICAMENTOS ANTIHISTAMÍNICOS; MONTE CARLO Y ESTUDIOS SEMI-EMPÍRICOS

In this article, we discussed about four antihistamine drug called promethazine, loratadine, cetirizine and buclizine. Promethazine in this list is the only one in first generation antihistamine classification with CNS sedation effect and the other three belongs to second generation antihistamine group which are nonsedation and used to treat in many different anti-allergenic fields. In the following we optimized potential, kinetic and total energy of these molecules at body temperature (310 k ̊) and environment temperature (298 k  ̊) using Mont Carlo method in Amber force field in 500 ns. The quantum mechanics calculations and molecular structure of these molecules investigated using B3LYP level of theory with 6-31 G (d) as a basis set. Theoretical computations were performed to study thermodynamic parameters and frequency analysis. Electronic, thermal, zero point and gibs free energy and enthalpy were estimated in frequency analysis. Semi empirical computations were summarized to pm3 method and different energy parameters (total energy, Binding Energy, Isolated Atomic Energy, Electronic Energy, Core–Core Interaction and Heat of Formation.


INTRODUCTION
Promethazine is in a group of drugs called phenothiazine (FEEN-oh-THYE-a-zeens) ,with C17H20N2S molecular formula and 284.42 g·mol −1 molecular mass, known by a first-generation antihistamine and blocks the effects of the naturally occurring chemical histamine in our body & Scherl ER et al, 1995.
In the treatment of allergenic prepuces ,Promethazine is used to cure allergy symptoms such as itching, migraine episodes (Buzdar et al, 1994), cancer Chemotherapy (Philpot et al,2000), runny nose, sneezing, itchy or watery eyes, hives, and itchy skin rashes and in some cases it also famous in prevention of motion sickness, and treats nausea , vomiting or pain after surgery and as a sedative or sleep aid (Davis et al, 1973), although the sedation related to first generation antihistamine use has been shown some compromise performance at school and at work, distracting during driving and the ability to handle tasks that require a high degree of concentration and alertness (Hughes et al, 1972).
In addition, studies of promethazine have been shown of this drug has the modification effects on the electrical activity in cardiac tissues and blocks the histamine-induced positive chronotropic response in rabbit atria (Mutschler et al, 2001).
Along with its needed effects, promethazine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur, they may need medical attention such as Convulsions , difficult or unusually fast breathing, fast heartbeat or irregular pulse, high fever, high or low (irregular) blood pressure, increased sweating, loss of bladder control (Scherl ER et al 1995).
Loratadine with C22H23ClN2O2 Molecular Formula and 382.88 g/mol g·mol −1 molecular mass known as a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1 receptors, orally effective, long-acting, and free of significant central and autonomic nervous system activity , is a medication used to treat allergies such as allergic rhinitis (hay fever) and hives , treat sneezing, runny nose, watery eyes, hives, skin rash, itching, and other cold or allergy symptoms, treatment of allergic cough, as well as in rhino conjunctivitis ( Fischer et al, 2006).
Loratadines safety and efficacy were evaluated in a 28-day study conducted in patients with chronic idiopathic urticaria (Barbey et al, 1999).
Loratadine was discovered in 1980 and came to market in 1988 (Kosoglou et al, 2000). It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system (Roth et al, 1987), but recently studies shown that Patients with severe hepatic would better start with a lower dose (Meltzer et al, 1995) and in 1993 was approved by the FDA. The drug continued to be available only by prescription in the U.S. until it went off patent in 2002 (Fischer et al, 2006). Loratadine metabolized primarily by the cytochrome P450 hepatic enzyme, CYP3A4, and secondarily by CYP2D6 quickly in the liver to desloratadine combination (Portnoy et al, 2004). Nexo Revista Científica / Vol. 33, No. 01, pp. 94-108 / Junio 2020 About the presence of compatible doses of loratadine in the blood , substances that act as inhibitors of the CYP3A4 enzyme such as ketoconazole, erythromycin, cimetidine, and furanocoumarin derivatives (found in grapefruit) lead to increased plasma levels of loratadine and desloratadine which this had clinically significant effects in controlled trials of higher-than-usual doses of loratadine (20 mg) (Tillementa et al, 2003) Loratadine is a tricyclic antihistamine, which has a threefold greater affinity for peripheral as compared with central histamine1-receptors.
Loratadine and cetirizine are the most commonly prescribed second-generation antihistamines and in comparison, with first generation antihistamine at recommended doses have been shown to lack the CNS depressant effects associated with traditional antihistamines by having low affinity for H1-receptors in the CNS in vitro or in vivo (Safi et al, 2015).
Sedating antihistamines can worsen these effects. Therefore, nonsedating antihistamines are the best treatment choice for allergic conditions. However, although most antihistamines designated to be nonsedating at the recommended dose, sedation can occur when higher doses are used (Martindale, 1996).
Loratadine is a promising antihistamine for individuals involved in skilled activity studies a single daily dose of 10 mg is unlikely to impair performance and such these clinical usefulness studies have made possibility of the treatment of patients in sensitive occupations such as those in control of public service vehicles (Scherl ER et al, 1995).In as much as the deficiency of CNS effects is superior when choosing an antihistamine for an ambulant patient, it is also important that a clinically effective dose regimen is utilized (Buzdar et al, 1994).Cetirizine with C21H25ClN2O3 and 388.89 g·mol −1 respectively as molecular formula and molecular mass ,known as an antiallergic treatment and the carboxylic acid metabolite of hydroxyzine crosses the blood-brain barrier only slightly, and for this reason, it considered sedating by the FDA, as reflected in its cautionary labelling with regard to driving or operating potentially dangerous machinery while taking it ,although as it said before in a much lesser degree than older antihistamines such as promethazine and has 600-fold or greater selectivity for the H1 receptor in comparison with a wide variety of other sites, such as muscarinic acetylcholine, serotonin, dopamine, and α-adrenergic receptors, among many others (Mutschler et al, 2001) and bound to albumin with high affinity, while α1acid glycoprotein and lipoproteins contribute much less to total plasma protein binding & Portnoy et al, 2004.
Cetirizine and its R-isomer (Levocetirizine) has the same activity base on Pharmacodynamic studies and in the skin when a weal and flare reaction was induced by histamine (100 mg/ml), single doses of 2.5 mg L-CTZ and 5 mg CTZ produced equivalent inhibition (Mutschler et al, 2001).studies have revealed that the antihistaminergic activity of the racemate is primarily due to levocetirizine (Portnoy et al, 2004). Hepatic metabolism of cetirizine is insignificant. Even so, the pharmacokinetics of cetirizine in patients with hepatic dysfunction are modified (Safi et al, 2015).
For the reason of the fact which Cetirizine cannot metabolized by the cytochrome P450 system, agents which inhibit or induce cytochrome P450 enzymes including theophylline, erythromycin, clarithromycin, cimetidine, or alcohol cannot interact with drug (Mutschler et al, 2001).

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Nexo Revista Científica / Vol. 33, No. 01, pp. 94-108 / Junio 2020 Moreover, the non-renal (mostly hepatic) clearance of levocetirizine is also significantly lower than that of dextrocetirizine (11.8 mL min −1 vs. 29.2 mL min −1 ). By the fact that levocetirizine is indeed the eutomer of cetirizine (Portnoy et al, 2004) also Cetirizine did not cause any severe adverse events and no patient was recede from treatment because of a harmful event Tillementa et al, 2003).
Buclizine with C28H33ClN2 molecular formula and 433.028 g/mol g·mol −1 molecular mass is a piperazine histamine H1 receptor antagonist with mainly antiemetic and antivertigo activities, binds to and blocks the histamine H1 receptor and so on preventing the symptoms of histamine activity. Buclizine apply its anti-emetic effect by binding to and blocking the muscarinic and histamine receptors in the vomiting center of the central nervous system (CNS), thereby this may prevent activation of the chemoreceptor trigger zone (CTZ) and may reduce nausea and vomiting (Martindale, 1996).
Studies demonstrated Buclizine is an N-alkylpiperazine carrying (4-chlorophenyl) (phenyl) methyl and 4tert-butylbenzyl groups. It was manufactured by Stuart Pharms and initially approved by the FDA in 1957. So on, it was admitted to be effective as an appetite stimulant in children when carried out in the syrup form, however, this symptom has not been validated. In addition to the above benefits, buclizine also has been studied in the treatment of migraine attacks (the drug is given in usual doses of 12.5 mg at the start of an attack or when one is known to be imminent) and in the treatment of nausea and vomiting during pregnancy (Portnoy et al, 2004) and also been used in the treatment of vertigo associated with disorders of vestibular system, although its value in these conditions remains to be established (Mutschler et al, 2001).
Morren and Strubbe prepared buclizine by mixing hydrochloric acid with 0.5 mol of 1-(p-tert-butyl benzyl)-piperazine 1, adding 0.5 mol p-chlorobenzaldehyde 2, and adding dropwise aqueous 0.55 M potassium cyanide, then heating on a water bath for 2 h, yields an addition product which is separated in toluene and dried before reaction with phenyl magnesium bromide 3 to give buclizine 4 (Portnoy et al, 2004). Nexo Revista Científica / Vol. 33, No. 01, pp. 94-108 / Junio 2020 Molecular mechanics calculations use to to predict the structure and properties of molecules features from classical physics rules, based on the descriptive model of the ball and spring, and are better interpreted for geometrical equilibrium than plastic models. It is low cost and limited to geometric equilibrium. (Tillementa et al, 2003).

All-atomistic molecular mechanics methods have the following properties:
 Each atom is simulated as one particle  Each particle is assigned a radius (typically the van der Waals radius), polarizability, and a constant net charge (generally derived from quantum calculations and/or experiment)  Bonded interactions are treated as springs with an equilibrium distance equal to the experimental or calculated bond length These equations together with the data (parameters) required to describe the behavior of different kinds of atoms and bonds, is called a force-field. Many different kinds of force-fields have been developed over the years. Some popular force fields such as Mm, Opls, Amber and bio+ will investigated in this article (Tillementa et al, 2003). Quantum mechanics (QM; also known as quantum physics, quantum theory, the wave mechanical model, or matrix mechanics), including quantum field theory, is a fundamental theory in physics which describes nature at the smallest including atomic and subatomicscales (Naghsh et al, 2018). Classical physics, the description of physics existing before the formulation of the theory of relativity and of quantum mechanics, describes nature at ordinary (macroscopic) scale. Most theories in classical physics can be derived from quantum mechanics as an approximation valid at large (macroscopic) scale (Safi et al, 2015).

COMPUTIONAL METHODS
The molecular structure, quantum mechanics and Theoretical computations, charges distribution and electronic, thermal, zero point and gibs free energy for Promethazine, Loratadine, Cetirizine, Buclizine at Frequency method (Monajjemi et al, 2019) calculated using B3LYP level of theory with 6-31 G (d) basis set with the gaussian 09 program. Gaussian 09 is a computational chemistry software package appropriate to demonstration interaction of electrons in atoms and molecules. Molecular orbital energies, bond energies, molecular geometries and energies, and vibrational frequencies are the other features can be found in this program (Pham et al, 2019& Safi et al, 2015. Kinetic and thermodynamic investigations, geometry optimization, Monte Carlo and vibrational analysis done by using HyperChem 8.0.8 software which is appropriate in both molecular mechanics (MM) and quantum mechanics (QM) computations and known by its sophisticated molecular modeling environment including, its quality, Flexibility, and ease of use and 3D embodiment (Portnoy et al, 2004). There will be three steps ahead in any quantum mechanical calculation in HyperChem 7.0 program package (Mutschler et al, 2001).
In the beginning, the molecule must be prepared by an appropriate starting geometry and compatible format (pdb, mol). Second, a calculation method and its associated (Setup menu) options must be chosen. At the end, there must be choosing of the type of calculations such as single point, geometry optimization, Monte Carlo and vibrational analysis (Portnoy et al, 2004).
Three important parameters including total energy, potential energy and kinetic energy in time of simulations 10 ns at two temperature (298 and 310 K degree) and in the Amber force field were also optimized data we extraction from Monte-Carlo simulation. 99 Nexo Revista Científica / Vol. 33, No. 01, pp. 94-108 / Junio 2020 Parameters such as Total Energy, Binding Energy, Isolated Atomic Energy, Electronic Energy, Core-Core Interaction and Heat of Formation are the best vibration analysis of molecules using a quantum mechanical approach that was obtained via pm3 method in Semi-empirical calculations (Mutschler et al, 2001).

3.RESULT AND DISCUSSION
In this article theoretically and geometry calculations, physical and chemical preparties of nuclear optimized by using three methods such as Mont Carlo, semi empirical and frequency.in the first section total, potential and kinetic energy in Mont Carlo calculations optimized in two different temperature 298, 310 kelvin degree (respectively environment and body temperature) in Amber force field and at 500 steps which came in table 1,2.
According to semi empirical-based calculations, our results were summarized to computation of total energy, Binding Energy, Isolated Atomic Energy, Electronic Energy, Core-Core Interaction and Heat of Formation obtained by pm3 method (table3). Computations were carried out to study thermodynamic parameters, frequency method and optimized geometrical parameters investigated using gaussian 09, B3LYP method and Uff/6-31G as the basis set that are listed in Table (table 4).
ε0 in frequency has been used to calculate total electronic energy: Sum of electronic and zero-point energies= ε0 + EZPE Sum of electronic and thermal energies= ε0 + Etot Sum of electronic and thermal enthalpies= ε0 + Hcorr Sum of electronic and thermal free energies= ε0 + Gcorr In the general look at the table 1 in 298 k˚, the kinetic energy in promethazine is the lowest one and after that loratadine with 44.4 kcal/mol, cetirizine with 46.1 kcal/mol and then buclizine with 56.8 kcal/mol are located. For potential energy, there is the minimized energy amount at the beginning of processing of cetirizine, promethazine and loratadine but with the steppes increasing, the more stability we get as it shown in table 1 these amounts for cetirizine in step 0 and 500 respectively is equal to 12.7 and 61.9 kcal/mol, for promethazine 23.1 and 53.9 kcal/mol and for loratadine23.9 and 64.5 kcal/mo. Indeed, potential energy at the step zero for buclizine 76.4 kcal/mol and at step 500 is 73.5 kcal/mol and the most value of this parameter is 92.2 kcal/mol in step 430.
For total energy in step 0 and 500 buclizine there is a value of 133.2 and 130.4kcal/mol, in cetirizine it is about 58.9and 108.1 kcal/mol, in loratadine 68.3 and 108.9 kcal/mol and for promethazine it is equal to 58.6 and 89.5 kcal/mol .Buclizine at the step 500 has the biggest value of total energy. Also, we can figure out that the most value of total energy in buclizine belongs to step 10 (143.4 kcal/mol), in cetirizine belongs to step 370 (107.3 kcal/mol) and for loratadine it belongs to step 140 (115.7 kcal/mol) and for promethazine belongs to step 370 (103.4 kcal/mol).
Based on table 2 ate 310 kelvin degree (the body temperature and the most important part of this investigation) kinetic energy in order from high to low value is equal to 59.13 kcal/mol (in buclizine) ,48.05 kcal/mol (in cetirizine), 46.2 kcal/mol (in loratadine) and 36.9 kcal/mol in promethazine.
For buclizine the minimized value of potential energy is in step 0 (73.6kcal/mol) and the maximum value is in step 230 (83.2 kcal/mol) and in step 500 is 67.6 kcal/mol .Also total energy in the beginning is 132.7 kcal/mol and at the end 126.7 kcal/mol and the maximum value is also in step 230 (142.4 kcal/mol). Nexo Revista Científica / Vol. 33, No. 01, pp. 94-108 / Junio 2020 Except buclizine with a reduction behavior of potential and total energy, cetirizine, loratadine and promethazine have opposite behavior as In cetirizine potential and total energy in step 0 respectively is equal to 61.9 and 110.3 kcal/mol and in step 500 is equal to, 62.6 and 110.6 kcal/mol and the maximum value with this order is 63.6 kcal/mol (in step 50) and 112.3 kcal/mol (in step 170).
In loratadine potential energy in step 0 has a value of 64.51 kcal/mol and in step 500 has a value of 64.53 kcal/mol and total energy in these steps is 110.71 and 110.74 kcal/mol. Potential energy in step 0 in promethazine has a value of 53.9 kcal/mol and in step 500 has a value of 59.5 kcal/mol and total energy in step 0 in has a value of 90.9 kcal/mol and in step 500 has a value of 96.9 kcal/mol and the both maximum amount of potential and total energy belongs to step 150 (67.5 and 102.7 kcal/mol).
Semi empirical results in the table 3 obtained that maximum energy of total and binding energy belongs to promethazine (respectively is -65270.2 and -4134.2 cal/mol) and minimum value of these energies belongs to buclizine (-102925.2 and-6616.2 cal/mol).
The next parameters have been checked in semi empirical are isolated atomic energy ,electronic energy ,heat of formation and core-core interaction which the maximum value of the amounts belongs to buclizine and respectively are equal to -96309.008 ,-963841.6 ,143.002 and 860916.4 cal/mol and the minimum values also are -327771.06 , -61135.9 , 105.181 and 446322.6 cal/mol and belong to promethazine .
As it figures out in figure 2, R 2 parameter in semi empirical method for our antihistamine molecules has a value of =0.97 for total energy, =0.90 for core-core interaction, heat of formation and binding energy, =0.82 for isolated atomic energy, = 0.92 for electronic energy.
In table 4, it has been observed that the most positive value of G (Gibbs free energy), ΔH (enthalpy) for buclizine was 0.67and 0.75 which was obtained from the B3LYP/6-31G method. But the highest total energy (Etot) of buclizine was also computed by B3LYP/6-31G basis set and the calculated amount was 0.61 (Kcal/mol). Buclizine has also the maximum value of Ezpe (0.59, Hcorr (0.61) and Gcorr(0.54).

CONCLUSIONS
In this work we study theoretically the structure features of buclizine, cetirizine, loratadine and promethazine. Molecular mechanic and quantum mechanics data including potential, total and kinetic energy, geometrical optimization and vibrational analysis have been investigated by using Mont Carlo and Semi empirical methods. Free Gibbs energy, enthalpy and total energy investigated by frequency with BL3YP method and 6-31G (d) levels of theory. Following conclusions are obtained from the current study: It is figured out in Mont Carlo study buclizine in both 298 and 310 k˚ at the end of process has the most potential energy and promethazine has the minimum value of potential energy in the both temperatures. Results came out from semi empirical obtained that binding energy is much more in promethazine as a result of more stable structure and the strongest connection of nuclear obtained in buclizine and breaking the buclizine bonds release more energy than others. According to the thermodynamic parameters, we find that the amount of Gibbs free energy (∆G), standard enthalpies (∆H) of buclizine is the most positive value.