Molecular parameters and the antimicrobial activity of some n-substituted amino acids

The concept of “drug likeness” is used when developing drugs for a potential biologically active substance, which must meet some specific criteria, in particular it should be bioavailable. The traditional method of “drug likeness” assessment is verification of compliance with Lipinski’s rule. Aim. To determine the compliance of the “drug likeness” concept for some N-substituted amino acids and identify the quantitative “structure – microbiological activity” relationships. Materials and methods. Using ChemOffice 2016 software the physicochemical parameters determining the bioavailability of some N-substituted amino acids were calculated. Determination of the possible correlations and quantitative ratios of the biological activity data experimentally obtained with the molar refraction (MR) values calculated was conducted using STATISTIKA 8 program. Results and discussion. All compounds studied in their physicochemical properties meet the requirements for new BAS at the stage of testing their biological activity (correspond to Lipinski’s rule). The dependence of the microbiological action of some N-substituted amino acids on MR is maximal for compounds, which MR value is in the range of 2.13-4.53. The growth of all microorganisms was observed for unsubstituted amino acids (MR < 2.8). The maximum activity of all compounds studied was observed against gram-positive ( B. subtilis and S. aureus ), and the less activity was against gram-negative microorganisms ( E. coli, P. vulgaris, P. aeruginosa ) and fungi ( C. albicans ). It may be associated with the structural peculiarities of the cellular wall. The MR values calculated correlate satisfactorily with the experimental data of the antimicrobial activity of compounds. Conclusions. Statistically significant values of MR correlation with the values of the antimicrobial activity of some N-substituted amino acids against the microorganisms studied have been determined. It quantitatively confirms the presence of the “structure – activity” relationship in this series of compounds.

Ключевые слова: корреляция; антибактериальное действие; N-замещенные аминокислоты Determination of the "structure -activity" relationship is widely used in modern chemistry of biologically active compounds to predict their possible pharmacological activity [1].
At the present stage of development of combinatorial synthetic pharmaceutical chemistry millions of new compounds have been obtained. The classical ways for assessing their chemical and pharmacological properties are expensive, and their speed is less than the speed of discovering new compounds [2]. At present, prediction of the pharmacological properties at the initial stages of research attracts more attention. The quantitative "structure-activity" relationships (QSAR) are successfully used to study the mechanisms of action of different compounds [3]. They play an important role in predicting certain types of activities and are widely used in modern studies when it is required to describe rapidly a significant number of the compounds synthesized [4][5][6].
The concept of "drug likeness" is used when developing drugs for a potential biologically active substance, which must meet some specific criteria, in particular it should be bioavailable. The traditional method of "drug likeness" assessment is verification of compliance with Lipinski's rule [7].
Molar refraction (MR) reflects the volume of all molecules contained in one mole of the substance and cha-racterizes the ability to polarization of all electrons located in it. It is practically independent of temperature and the aggregation state of a substance; therefore, it can be successfully used for determination of the dipole moments of molecules, the study of the molecular structure, formation of hydrogen bonds, etc. [8].
The aim of the work is to determine the compliance of the "drug likeness" concept for some N-substituted amino acids and identify the quantitative "structuremicrobiological activity" relationships.

Materials and methods
Previously [9] the microbiological activity of some N-substituted amino acids 1-12 was studied (Tab. 1), the values of distribution coefficients for these compounds were calculated, then using the values obtained, the possible quantitative ratios were determined, and the "structure -activity" relationships revealed in this series with the experimental data of the antimicrobial activity were discussed [10].
To determine compliance with Lipinski's rule the physicochemical parameters determining the bioavailability of some N-substituted amino acids 1-12 (Tab. 2) were calculated using ChemOffice 2016 software, in particular Chem3D Ultra 16.0 [11].

Results and discussion
All compounds studied in their physicochemical properties meet the requirements for new BAS at the stage of testing their biological activity (correspond to Lipinski's rule) (Tab. 2).
In general, the statistical sampling included 12 compounds. During the statistical processing of the research results when analyzing a sample with the length of 12 cases the values of Pearson correlation coefficients more than 0.40 (р ≤ 0.05) are considered to be statistically significant [14].
The dependence of the microbiological action of compounds 1-12 on MR has a nonlinear character, and reaches the maximum values for compounds, which MR value is in the range close to the mean value (2.13-4.53) (Tab. 1, 2). The growth of all microorganisms was observed for unsubstituted amino acids (compounds 1, 5 and 9) with MR values less than 2.8. The maximum activity of all compounds studied was observed against gram-positive (B. subtilis and S. aureus), and the less activity was against gram-negative microorganisms (E. coli, P. vulgaris, P. aeruginosa) and fungi (C. albicans). It may be associated with the structural peculiarities of the cellular wall [15].
The analysis of the statistical processing of the results obtained indicates that the MR values calculated correlate satisfactorily (% , negative values of correlation coefficients) with the experimental data of the antimicrobial activity of compounds 1-12 in relation to S. aureus (r = -0.73481), E. coli (r = -0.75928), P. vulgaris (r = -0.77000), P. aeruginosa (r = -0.71342), B. subtilis (r = -0.76287), and Cl. Perfringens (r = -0.74181); they are statistically significant (Fig. 1-7). The relationship is absent only in the case of C. albicans (r = -0.13588), and its possible causes are mentioned above [15].
These combinations of Pearson correlation coefficient and the significance values indicate the reliability of plots 1-7 and equations given in Fig. Therefore, the earlier considerations [9,10] about the presence of the "structure -activity" relationship and the degree of its manifestation were confirmed quantitatively by calculations. The results obtained allow to predict the presence and the level of detection of the biological action of some N-substituted amino acids and