**6. Computational methods used in the design of bitterless prodrugs for bitter tastant drugs**

Nearly sixty five years ago, organic, bioorganic and medicinal chemists alike have started using computational methods for calculating molecular properties of ground and transition states. These computational methods use principles of computer science to aid in solving chemical problems. Theoretical results emerged from these methods, incorporated into efficient computer programs, for calculating the structures and physical and chemical properties of molecules.

Equilibriums energy-based and reactions rates calculations for systems having medicinal interests are of a vast importance to the health community. Today, quantum mechanics (QM) such as *ab initio*, semi-empirical and density functional theory (DFT), and molecular mechanics (MM) are commonly and increasingly being used and broadly accepted as precise tools for predicting structure-energy calculations for drugs and prodrugs alike [109-112].

*Ab initio* methods typically are adequate only for small systems. Ab initio methods are based entirely on theory from first principles. The ab initio molecular orbital methods (QM) such as HF, G1, G2, G2MP2, MP2 and MP3 are based on rigorous use of the Schrodinger equation with a number of approximations. Ab initio electronic structure methods have the advantage that they can be made to converge to the exact solution, when all approximations are sufficiently small in magnitude and when the finite set of basis functions tends toward the limit of a complete set. The convergence is usually not monotonic, and sometimes the smallest calcula‐ tion gives the best result for some properties. The disadvantage of ab initio methods is their enormous computational cost. They take a significant amount of computer time, memory, and disk space [109-112]. On the other hand, empirical or semi-empirical methods are less accurate because they employ experimental results, often from acceptable models of atoms or related molecules, to approximate some elements of the underlying theory. Example for such methods is the semi-empirical quantum chemistry methods based on the Hartree–Fock formalism, but make many approximations and obtain some parameters from empirical data. These methods are especially important for calculating large molecules where the full Hartree–Fock method without the approximations is too expensive. Semi-empirical calculations are much faster than their ab initio counterparts. Their results, however, can be imprecise if the molecule being computed is not similar enough to the molecules in the database used to parameterize the method. Among the commonly used semiempirical methods are MINDO, MNDO, MINDO/3, AM1, PM3 and SAM1. Calculations of molecules exceeding 60 atoms can be handled using semiempirical methods [113-116].

between two oxygens in rigid systems as investigated by Menger [63, 69-75],and (e) proton transfer from oxygen to carbon in some of Kirby's enol ethers [78-84]. The conclusions emerged from these studies are (1) the driving force for enhancements in rate for intramolecular processes are both entropy and enthalpy effects. In the cases by which enthalpy effects were predominant such as ring-closing and proton transfer reactions proximity or/and steric effects were the driving force for rate accelerations. (2) The nature of the reaction being intermolecular or intramolecular is determined on the distance between the two reacting centers. (3) In SN2 based ring-closing reactions leading to three-, four-and five-member rings the *gem*-dialkyl effect is more dominant in processes involving the formation of an unstrained five-member ring, and the need for directional flexibility decreases as the size of the ring being formed increases. (4) Accelerations in the rate for intramolecular reactions are a result of both entropy and enthalpy factors. (5) An efficient proton transfer between two oxygens and between nitrogen and oxygen in Kirby's acetal systems were affordable when a strong hydrogen bonding was developed in the products and the transition states leading to them [85-103].

In the past few years some prodrugs based on the trimethyl lock system have been reported. Borchardt et al. has shown that the pro–prodrug 3-(2'-acetoxy-4', 6'-dimethyl dimethyl) phenyl-3, 3-dimethylpropionamide is capable of releasing the biologically active amine drug upon acetate hydrolysis by enzyme triggering. Another successful example exploiting a stereopopulation control model is the prodrug Taxol which enhances the drug water solubility and hence affords it to be administered to the human body *via* intravenous injection. Taxol is the brand name for paclitaxel, a natural diterpene, approved in the USA

**6. Computational methods used in the design of bitterless prodrugs for**

Nearly sixty five years ago, organic, bioorganic and medicinal chemists alike have started using computational methods for calculating molecular properties of ground and transition states. These computational methods use principles of computer science to aid in solving chemical problems. Theoretical results emerged from these methods, incorporated into efficient computer programs, for calculating the structures and physical and chemical properties of

Equilibriums energy-based and reactions rates calculations for systems having medicinal interests are of a vast importance to the health community. Today, quantum mechanics (QM) such as *ab initio*, semi-empirical and density functional theory (DFT), and molecular mechanics (MM) are commonly and increasingly being used and broadly accepted as precise tools for

*Ab initio* methods typically are adequate only for small systems. Ab initio methods are based entirely on theory from first principles. The ab initio molecular orbital methods (QM) such as HF, G1, G2, G2MP2, MP2 and MP3 are based on rigorous use of the Schrodinger equation with

predicting structure-energy calculations for drugs and prodrugs alike [109-112].

for use to treat cancer [104-108].

412 Application of Nanotechnology in Drug Delivery

**bitter tastant drugs**

molecules.

Another widely used quantum mechanical method is the density functional theory (DFT). With this theory, the properties of many-electron systems can be determined by using functionals, i.e. functions of another function, which in this case is the spatially dependent electron density. Therefore, the name density functional theory comes from the use of functionals of the electron density. DFT is among the most popular and versatile methods available in condensed-matter physics, computational physics, and computational chemistry. The DFT method is adequate for calculating structures and energies for medium-sized systems (30-60 atoms) of biological, pharmaceutical and medicinal interest and is not restricted to the second row of the periodic table [43].

Although the use of DFT method is significantly increasing some difficulties still encountered when describing intermolecular interactions, especially van der Waals forces (dispersion); charge transfer excitations; transition states, global potential energy surfaces and some other strongly correlated systems. Incomplete treatment of dispersion can adversely affect the DFT degree of accuracy in the treatment of systems which are dominated by dispersion.

On the other hand, molecular mechanics is a mathematical approach used for the computation of structures, energy, dipole moment, and other physical properties. It is widely used in calculating many diverse biological and chemical systems such as proteins, large crystal structures, and relatively large solvated systems. However, this method is limited by the determination of parameters such as the large number of unique torsion angles present in structurally diverse molecules [117].

Molecular mechanics simulations, for example, use a single classical expression for the energy of a compound, for instance the harmonic oscillator. The database of compounds used for parameterization, i.e., the resulting set of parameters and functions is called the force field, is crucial to the success of molecular mechanics calculations. A force field parameterized against a specific class of molecules, for instance proteins, would be expected to only have any relevance when describing other molecules of the same class. These methods can be applied to proteins and other large biological molecules, and allow studies of the approach and docking of potential drug molecules Since the size of the system which *ab initio* calculations can handle is relatively small despite the large sizes of biomacromolecules surrounding solvent water molecules such as in the cases of enzymes and receptors, isolated models of areas of proteins such as active sites have been investigated using *ab initio* calculations. However, the disre‐ garded proteins and solvent surrounding the catalytic centers have also been shown to contribute to the regulation of electronic structures and geometries of the regions of interest. To overcome these discrepancies, quantum mechanics/molecular mechanics (QM/MM) calculations are used, in which the system is divided into QM and MM regions where QM regions correspond to active sites to be studied and are described quantum mechanically. MM regions correspond to the remainder of the system and are treated molecular mechanically. The pioneer work of the QM/MM method was accomplished by Warshel and Levitt [118], and since then, there has been a significant progress on the development of a QM/MM algorithm and applications to biological systems [119,120].

cluster of water the dissociation of the tetrahedral intermediate was the rate-limiting step. When the leaving group (methylamine) in **34**-**42** was replaced with a group having a low pKa value the rate-limiting step of the hydrolysis in water was the formation of the tetrahedral intermediate. In addition, the calculations revealed that the efficiency of the intramolecular acid-catalyzed hydrolysis by the carboxyl group is remarkably sensitive to the pattern of substitution on the carbon–carbon double bond. The rate of hydrolysis was found to be linearly correlated with the strain energy of the tetrahedral intermediate or the product. Systems having strained tetrahedral intermediates or products experience low rates and vice versa

**H2O**

**34**; R1=R2=H **35**; R1=R2=Me **36** ;R1=H; R2=Me

; R1=H; R2=Et ; R1=H; R2=n-Propyl ; R1=H; R2=Trifluoromethyl ; R1=R2= Trifluoromethyl

**O**

**R1**

**R2**

**37**; R1,R2 CycIopent-l-ene-1,2-diyl **38**; R1, R2 Cyclohex-l-ene-1,2-diyl

**8. Bitterless atenolol prodrugs based on Kirby's maleamic acids enzyme**

Atenolol is a relatively polar hydrophilic compound with water solubility of 26.5 mg/mL at 37

C and a log partition coefficient (octanol/ water) of 0.23. Atenolol is a selective ß1-adrenoceptor antagonist, applied in the treatment hypertension, angina, acute myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and the symptoms of alcohol with‐ drawal. The net effect of atenolol on controlling both the heart rate and blood pressure is the reduction in myocardial work and oxygen requirement which reduces cardiovascular stress,

Atenolol has a pKa of 9.6; it undergoes ionization in the stomach and intestine thus its oral

bioavailability is low due to inefficient absorption through membranes.

**O**

Prodrugs for Masking the Bitter Taste of Drugs

http://dx.doi.org/10.5772/58404

415

**O**

**NH2CH3**

[51,52,54,91].

**R1**

**R2**

**model**

0

**NHCH3**

**Figure 5.** Acid-catalyzed hydrolysis of maleamic acids **34**-**42**.

thereby preventing arrhythmia and angina attacks.

**OH**

**O**

**O**
