Determination With QSAR of Biological Activity and Relations of Between Molecular Descriptions of 5,8-Quinolinequinones Derivatives

In this study, some electronic, hydrophobic and termochemical parameters of 28 different 5,8-quinolinequinones derivatives having diversity substituents have been calculated by using DFT (B3LYP) / 6-31G (d, p) method and basis set. Relationships between different molecular descriptives have been studied with used like molecular polarizability (α), dipole moment (μ), E HOMO , E LUMO , molecular volume (V m ), ionization potential (IP), electron affinity (EA), electronegativity (χ), molecular hardness (η), molecular softness (S), electrophilic index ( Ꞷ ), molar refractivity (MR), octanol – water partition coefficient (log P ), thermochemical properties (entropy (S e ), capacity of heat (C)); as to investigate activity relationships with molecular structure. In addition, The QSAR/QSPR between molecular properties and biological activity (Anti-proliferative and Anti-inflammatory activity) has investigated, where R, R 2 , F and P have taken into account in order to find a statistically correct model in QSAR studies. The dependence of the electronegative parameter on both electronic and thermochemical parameters was the most correlated parameter.

QSARs (Quantitative structure-effect relationships) / QSPRs (Quantitative structureproperty relationships) is a mathematical expression showing the biological activity according to structural definitions of the series of homologous molecules. However, QSAR/QSPR can predict of the properties of a wide range of chemical compounds based on the correlation between biogical activity and molecular descriptors. The main objective of QSAR is to develop new molecules with desired properties by using statistical calculations results with computational values such as chemical, physical, topological and molecular properties. The molecules having desired properties are available when appropriate results can found. Thus, the QSAR methodology develops and accelerates processes in the development of novel molecules and drugs. In the QSAR and QSPR process have used to definitions related to topology, thermodynamics, quantum chemistry, shape and electronic energy. In particular, the net atomic load, HOMO-LUMO energies, orbital electron densities, and super-delocalizable diets are related to various biological activities [7][8][9][10][11].
The investigated 5,8-Quinolinequinones derivatives have previously been experimentally reported in the literature for their anti-proliferative and anti-inflammatory activities [6]. However, there are no studies in the literature on QSAR / QSPR study of 28 5,8-Quinolinequinones derivatives. In this case, it has been a source of motivation to do this study. In this present work, QSARs/QSPR between different biological activity values, such as anti-cancer and anti-inflammatory [6], and a lot of physicochemical parameters of the some 5,8-quinolinequinones derivatives have been investigated with remove multi linear regression analysis. Relationships between calculated molecular descriptors were analyzed and interpreted by quantitative methods.
Then, the relationship between the calculated molecular descriptors was investigated.

Statistical Methods
Afterwards, remove multiple linear regression method is used to investigated quantitative structure-activity relationships (QSARs) between different biological activity values and different physicochemical parameters. This statistical method has been applied by using the statistical software SPSS 15.0 program [17].

Molecular Definitions
In table 1 have tabulated to molecule number and IUPAC names of 5,8-Quinolinequinones derivatives. Table 2 have been listed to molecular descriptions belong to investigated compounds. Relationships between molecular descriptions calculated independently from each other have been examined in Figure 2, and correlation graphs of the changes between them have given.
While the volume of a molecule gives information about the size of the molecule, it changes in proportion to the size of the substituent added. Thus, compound number 1 has been found with the smallest volume (138.40 cm 3 /mol), while the volume of compound number 3 has been found (114 cm 3 /mol). The volume of the quinone ring was found to be smaller than the other molecule because the amino group in the 6 position of 3. molecule is inductively attracted by the quinone ring. The volume of the 28. molecule has been found to be the largest. As can be seen from figure 1, this molecule is due to the toluene-4-sulfonyl substituent at the 6,7 position added large volume substituent.
The dipole moment is directly related to the electronic structure of the molecules and the energy caused by the electronic structure. It was observed by Lien et al. that dipole moment is an important parameter for drug-receptor interactions. Interaction of drugs or vitamins of receptors have been occurred to the interaction with electronic structure. For example, dipoledipole, dipole-induced dipole and induced dipole-induced dipole [18]. In our study, the 24th compound has the largest dipole moment among investigated 5,8-Quinolinequinones derivatives, which is founding as 7.14 D dipole moment value due to the electronegative atom in its 7th position, Cl and containing sulfonyl group substituents. This compound has the major anti-proliferative activities. On the other hand, it is seen from Table 3 that the 8th molecule with the lowest dipole moment value of 0.74 D really has the lowest experimental logIC50 value. When we look at the dipole moment of the investigated it is that the smallest and largest dipole moment is compatible with the biological activity.
The log P value is parameter of soluble in the Water / octanol system for a molecule. Less dissolution and less transport are the main reason for failure in the process of developing drugs [19][20][21][22][23][24][25][26]. As a result, molecules with a high logP value have greater biological activity than those with low log P and can reach the receptor through the cell membrane. Negative log P value of the molecule in the hydrophilic properties, that is, they can interact more easily in the aqueous environment, if logP = 0, it has affinity both in the aqueous and in the oil environment. The molecule with a positive logP value can dissolve in high concentrations in its lipophilic environment. Thus, we can say that the substituents added to the quinoline ring have a direct effect on the logP value. While 1, 20, 21, 22 and 23 molecules as seen from Table 2  The definition of MR is related to the polarity and size of a substituent that binds to the molecule. The larger the polar portion of a molecule, the greater the molar refractivity [27].
Molar refractivity is the size that describes the separator power that aids the interaction between the biological receptor and the substituent. MR also shows a measure of the molecular volume. Consequently, the MR is a measure of the capacity of the substituent that modifies the receptor conformation that does not want to interact with the substrate [28]. As seen in Table 2, the highest MR value have found in the 28th molecule, while the lowest value has found in the 5th molecule. It can be seen from Table 3 that experimentally HL60 logIC50 (pIC50) has the highest value. As seen in Table 2, the highest MR value was found in the 28th molecule, while the lowest value was found in the 5th molecule. It can be seen from Table 3 that HL60 logIC50 (pIC50) has experimentally the highest value. In that, 28 Molecular polarizability has been determined as (1) intermolecular weak interactions between closed shell species, and (2) for different molecular properties such as boiling points, melting points, vaporization enthalpies, solubilities, and solvent polarity scales. In addition, it measures the response of the outer shell electrons of a molecule toward an external perturbation, whereas chemical binding can be also viewed as a result of reorganization of the valence electrons of atoms due to perturbation effects [31]. The 28th molecule has the highest polarizability value, while the 3rd molecule and the 1st molecule have the lowest value. As can be seen from Figure 2, between average polarizability and volume, molar refractivity, heat capacity, R 2 =0.8105, R 2 =0.7905 and R 2 = 0.9189, respectively.
Electronegativity (χ) as Pauling, the molecule itself to attract electrons described as the power of an atom in the molecule [32]. Defined as in the following equation [33], As seen in Table 2, Electronegativity is the 1>2>28 molecules according to high electronegativity parameter, which can react with any electron. This situation is compatible with other parameters indicating biological activity. At the same time, as can be seen from LUMO also indicate to areas having possible electrophilic and nucleophilic interaction in molecule, respectively. In this case, Compound 1 has both electrophilic effect and nucleophilic effect among the investigated compounds. As seen in Figure 1S in Supplementary Materials, green areas are positive value, when blue areas are negative value HOMO-LUMO shape. The electrophilic on positive charge groups or atoms their attack to the most likely to the atomic site with a high density of orbital HOMO, while nucleophilic on negative charge groups or atoms attack LUMO that is correlated with atomic high density of orbital LUMO [34][35][36]. There are changes in the HOMO and LUMO fields depending on the substitution added. As seen in Figure 1S, there are changes in the HOMO and LUMO fields depending on the substitution added.
Chemical hardness (η) is related to the stability of the molecule. It is defined as in the following equation [22]. Global Electrophilicity Index (ω) have been described the electrophilic index as a measure of the energy falling due to the highest electron flow between the donor-acceptor molecules [24]    2 2  Global electrophilicity has a high (low) electrophilicity index when two molecules react as one acts as an electrophile (nucleophile). The electrophilicity is the measure of the stability in the energy when the system gains an additional electronic load from the environment.
Electrophilicity is the definition of reactivity that allows the quantification of a global electrophilic index of a molecule in a relative measurement scale [25][26][27][28][29][30]. The global electrophilic index of the 1. molecule is large compared to other molecule. Thus, when the 1. molecule exchanges electrons, it becomes more stable and the total energy of the molecule is optimized. It is possible that the 1. molecule interacts with its environment in electrophilic ways.

QSAR
In Table 3 Table 2 are listed. The observed biological activity values, calculated biological activity values and physicochemical parameters of these molecules are listed in Table 3. The QSAR models for anti-proliferative activity values, which is HL 60 pIC50 and T-cells pIC50, and for anti-inflammatory activity (pAI50) can see from 1, 2 and 3 equations, respectively. An ideal method derived with MLRA is one that has high correlation coefficient square (R 2 ≤0.7), correlation coefficient (R≤0.8), high ability for prediction (P≤0.05) and high F statistic value. The correlation graphs of calculated biological activities with experimental biological activities values have shown in Figure 3.
As can be seen from Eq.(1) that anti-cancer activity (HL60) depends theoretically on positive electrophilic index and heat capacity, while it depends on negatively Ionization potential, LUMO energy, mean of polarizability, molecular volume and entropy.

Conclusions
In this study, some physicochemical parameters of 28