Reactivity of O-Drug Bond in some Suggested Voltarine Carriers: Semiempirical and ab Initio Methods

In this work, the possibility to use new suggested carriers (D= Aspirin, Ibuprofen, Paracetamol, Tramal) is discussed for diclofenac drug (voltarine) by using quantum mechanics calculations. The calculation methods (PM3) and (DFT) have been used for determination the reaction path of (O-D) bond rupture energies. Different groups of drugs as a carrier for diclofenac prodrugs (in a vacuum) have been used; at their optimized geometries. The calculations included the geometrical structure and some of the physical properties, in addition to the toxicity, biological activity, and NLO properties of the prodrugs, investigated using HF method. The calculations were done by Gaussian 09 program. The comparison was made for total energies of reactants, activation energies, and transition states to final products. The suggested prodrugs aim to improve the diclofenac carrier's properties and obtain new alternatives for the approved carriers theoretically.


Introduction:
Ab initio, quantum chemistry has long been used as an essential tool for investigating the structure, stability, kinetics of reactions, and mechanisms of various molecular systems. Ab initio, calculations based on the Schrödinger equation have the advantage of being based only on the fundamental laws of physics and universal constants. Therefore, the calculations do not need any empirical constants. The use of ab initio calculations has become an essential method in recent years to understand the chemical properties of corrosion, prodrugs, and other applications )1,2). The semi-empirical theory (PM3) developed by Dewar and coworkers (3)(4)(5)(6) considered the success of molecular cloning, the repetition of molecular structures, and the analysis of chemical reactions. Non-steroidal antiinflammatory drugs (NSAIDs) are one of the world's most widely used classes of medicines used to treat pain, fever, and inflammation (7). Nowadays, one of the significant challenges facing the pharmaceutical industry is to discover new drugs to treat chronic inflammation without adverse effects. Diclofenac and its various salts are well-known non-steroidal anti-inflammatory drugs (NSAIDs), often used orally, topically and parenterally to treat a wide range of inflammatory conditions (8). Prodrugs have many advantages over their parent products, are designed to improve the physicochemical and pharmacokinetic properties of their parent active drugs, and thus to boost their oral absorption, water solubility, bioavailability; reduce their toxicity and/or bitter sensation (9)(10). Kubba et al. have theoretically studied the rupturing of O-R bond in some ampicillin, cefuroxime and cefpodoxime derivatives containing various substitute organic groups, using quantum mechanical calculations of semiempirical PM3 and (UHF) methods, in an attempt to show which of these groups could be used as a good carrier link for them (11)(12)(13). The main side effect of NSAID's is their gastric acidity, due to released free H + . On the other hand, all NSAIDs have free -COOH (carboxylic acid) group which works by competitive cyclooxygenase enzyme inhibition (COX1/COX2). The purpose of this project is to transform the free (COOH) of diclofenac into a prodrug of ester (of drugs carrier (COOD)) with sensitive drugs as a carrier (14).

Results and Discussion:
Ground state of the molecular structure: The results calculated from PM3 and U-DFT for the (bond lengths Å) of the studied diclofenac prodrugs to drugs as carries (Aspirin, Ibuprofen, Paracetamol, and Tramadol) at the equilibrium geometry are shown in Table 1. The tabulated results showed that the difference for (O-D) (D= Asp, Ibu, Prm, and Trm.) bond was slightly shorter or slightly longer. The extensive studies focused on the bond length of (O-D), where (D represents C21). The bonds length of OD of the Pro.Dc (1-4) calculated by PM3 and U-DFT/STO-3G were in the range of (1.369 to 1.437 Å). The O-D bond length with (Ibu) carriers is shorter than O-D bond length of Pro.Dc (Asp, Prm, Trm). This difference in the length of the bonds is due to the spatial arrangement and the number of different atoms in these molecules (20). The shortest bond length of OIbu (1.369 Å) for the Pro.Dc (Ibu) leads to expect that it has the most significant rupture

Examination of geometrical optimization structures:
Pro. Dc (D) of the studied Drugs with carriers (of Aspirin, Ibuprofen, Paracetamol, and Tramadol) showed a decrease in total energy in the order of (Ibu< Trm< Prm< Asp). At the same time, Pro. Dc.(D) of (Asp, Ibu, Prm, Trm) compounds showed an increase in dipole moment (μ) in the order of (Prm> Ibu> Trm> Asp) see (Tables 2,3) directly proportional to the size of the molecular and the different in geometrical of the studied compounds (21). In addition, there is a decrease in E LUMO and E Gap with an increase in dipole moment (μ). Therefore, they are probably more stable and more viable to use as a carrier linkage for diclofenac drug. Further, there is a decrease in E tot with the increasing in the length of the bond of the Ibu, Par, and Trm respectively.

O-D bond rupture energies calculations:
The coordinate reaction method (where O-D bond was controlled to an applicable degree of freedom and other bonds lengths were freely optimized) (22) was used to calculate O-D bond rupture energy for (Asp, Ibu, Pra and Trm). In this method, one bond length is constrained for the appropriate degree of freedom, while the other internal coordinates are freely optimized. The activation energy values of O-D bond rupture calculated the difference in energy for global minimum structure and derived transition state (t.s). Eenergies of reactants, products, and transition states were calculated and studied using PM3 and U-DFT methods. All calculations done without using solvents. It was essential to reinsert the shape of the reaction curve and extend the treatment to ester and anhydride derivatives of diclofenac drug. The treatment showed a change in curve energy with the reaction path, activation energy, and structures of transition states as well as the reaction products. The results of O-D bond rupture energies of diclofenac esters prodrugs are shown in Tables  3,4.    The suggested carriers (Dc.Asp, Dc.Prm) did not produce the acid drug as a final product of O-D bond rupturing, but produced, instead two free radical molecules in the intermediate step in reversible rupture reaction, Fig. 6  The suggested prodrugs of drugs carriers (Dc.Ibu, Dc.Trm) adopt irreversible reaction for O-D bond rupture Fig. 7, and produced acidic product. The ΔHc and ∆E are a positive value (endothermic reaction) ranging from (16.13793 to 3.800498 kcal/mol) for PM3 and from (46.73344 to 11.7236 kcal/mol) for DFT Tables (3,4). In comparison with common diclofenac prodrug, (Dc.Na, Dc.K) showed ΔHc range (-0.614 to -33.723 kcal/mol), and ∆E (-5.153 to -5.624 kcal/mol) with activation energy Ea # (3.909, 7.802 kcal/mol) respectively by PM3 and (15.513, 17.012 kcal/mol) by DFT. These results were obtained for all the derivatives, which were given the acid drug. The derivative Dc.Trm, was found in a good prodrug due to low values of ΔHc, ∆E (3.800498, 11.7236 kcal/mol), respectively, middle activation energy Ea # (52.10722, 60.48958 kcal/mol) by PM3 and DFT Fig. 5. The breakage of O15-C21 bond was at a bond length of 1.4 Å, leading to form cation and anion fragment. The activation energy range is (54.98051 to 52.10722) kcal/mol. The transition state was at the bond length 2.2 Å product fragment at 2.3 Å, Fig. 11. Proportion to the activation and cracking energies of O-D bond (D= Ibu, Trm) of these carriers, would hopefully be present for these drugs to be good link carriers.   Table  5. The predicted results give a possibility of using the suggested carriers as a non-toxic with diclofenac prodrug at the maximum of these concentrations (23). For HF descriptors, several equations were generated, and by using all the variables, the statistically best model is the fourparameter formula, as shown below: HF-LogLC50=38.00 -1.13Str +1.38x10 -3 ω H -2.22x10-3 ω L -0.36IA (18) S tr = Translational entropy, ω= vibrational wavenumber, I A = principal moment of inertia.

Predicted biological activity of prodrugs (19):
Quantum chemical calculations were used to investigate the biological activity of the calculated compounds by using HF method. The biological processes usually take place in an aqueous medium. Depending on quantum chemical calculations, the time and material costs involved in practical experiments can be reduced. The calculated quantum chemical descriptors were compared with each other. These parameters are listed in Table 6. Dc.Asp > Dc.Prm > Dc.Trm > Dc.Ibu According to the high ranking, there is no general ranking but Dc.Asp seems to be the most reactive prodrug. The Dc.Ibu is the second. Dc.Prm and Dc.Trm is approximately of the same biological activity region. These parameters show the biological activity and changing according to the target cell, medium, and structure of biological material or interaction region Fig. 12. Dc.Asp, Dc.Ibu, Dc.Prm and Dc.Trm showed heaving in electron density that leads to high the biological activity. Moreover, these results give excellent initial suggestions.

Dc.Asp
Dc.Ibu Dc.Prm Dc.Trm Figure 12. MEP maps of the investigated prodrugs (in aqueous solution). Fig. 12 with range (-9.050 to 9.050) represents the electron density regions, whereas the red color indicates the region of high electronic density, and the blue color represents the region of low electronic density. The region of donating and accepting electrons is the green region, and the nearer region to a red color is the region of low electron density.

Investigations of non-linear optical (NLO) properties:
Vacuum medium was used to calculate NLO properties. The urea was considered as a reference in these investigations (19,24). The determination of activity of a molecule based on some parameters, nonlinear optical properties are relevant.