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QSAR Study of 2-benzylthiopyrimidine Derivatives with Antibacterial Activity on Staphylococcus Aureus

Amon Benjamine ASSOMA*, Siomenan COULIBALI, Tchambaga Etienne CAMARA, Patrick-Armand ACHI, Ane ADJOU

Laboratoire de Constitution et Réaction de la Matière, UFR Sciences des Structures de la Matière et Technologie, Université Félix Houphouët-Boigny de Cocody, 22 BP 582 Abidjan 22, Côte d’Ivoire

Abstract: This work presents a Quantitative Structure-Activity Relationship (QSAR) study of twenty new 2-benzylthioprymidine derivatives that possess antibacterial activity. The antibacterial activity of these compounds was evaluated on a multi-resistant Staphylococcus aureus (S. aureus) strain. The concentrations that inhibit 50% of S. aureus (IC₅₀) were determined as antibacterial parameters by the microdilution method. The results revealed that all the synthesized compounds showed significant antibacterial activity against the tested germ. A mathematical relationship was established by Non-Linear Multiple Regression (NLMR) between the potential inhibitory concentration (PIC₅₀) of the twenty compounds and physicochemical parameters such as the Partition coefficient (LogP), the Molar Volume (MV), the Ionisation Potential (IP), the Electronic Affinity (EA) and the Carbon-Sulfur bond length [l(C-S)]. This mathematical relationship will be used to predict the antibacterial activity of other 2-benzylthioprymidine derivatives.

Keywords: partition coefficient, molar volume, QSAR, antibacterial activity

Received July 22, 2022; Revised August 24, 2022; Accepted September 05, 2022

Citation: Amon Benjamine ASSOMA, Siomenan COULIBALI, Tchambaga Etienne CAMARA, Patrick-Armand ACHI, Ane ADJOU, QSAR Study of 2-benzylthiopyrimidine Derivatives with Antibacterial Activity on Staphylococcus Aureus. Journal of Materials Physics and Chemistry, 10 (2). 36-42. January 2022. doi:10.12691/jmpc-10-2-1

1. Introduction

Bacteria, viruses, parasites, and fungi are responsible for infectious diseases that are classified as the leading cause of death in developing countries with 50.000 cases of death per day [1]. Among these diseases, bacterial infections caused 70 % of deaths [2]. The studies reported showed the ineffectiveness of antibacterial against several bacterial strains, notably S. aureus. Some strains of S. aureus are pathogenic and multidrug-resistant. The one used in this study is resistant to Amoxicillin, Ampicillin, Oxacillin, Ceftazidime, Fosfomycin, Vancomycin, and Cefsulodin [3,4,5,6]. Faced with resistance problems, the pharmaceutical industry is increasingly interested in new compounds with considerable added value in terms of better treatment of serious public health problems. This development of new compounds was mainly oriented towards bioactive heterocyclic compounds. To contribute to the search for new effective antimicrobial agents, our research team synthesized twenty 2-benzylthiopyrimidine derivatives and evaluated the antibacterial activity on this S. aureus strain [7,8]. Indeed, this work focused on the pyrimidine scaffold while its exhibited several biological properties, namely antiviral [9], antimicrobial [10], anti-tuberculosis [11], analgesic [12], also used as antihypertensive [13] and, antitumor agent [14]. The 2-thiopyrimidines are obtained by replacing the oxygen atom linked to the C-2 carbon of pyrimidine moiety with a sulfur atom. These compounds are the most widely used and also possess biological properties, such as antimicrobial [15,16,17], antiviral [18], anti-inflammatory [19] and, antitumor [20].

To predict the antibacterial parameters (PIC₅₀) of 2-benzylthiopyrimidine derivatives, we used the Quantitative Structure-Activity Relationship (QSAR) method. This method consists in finding a correlation between an antibacterial parameter measured for a panel of compounds and some molecular descriptors. The aim of this work is to find, from the Non-Linear Multiple Regression (NLMR), a correlation between the antibacterial activity of the twenty 2-benzylthiopyrimidine derivatives, evaluated on S. aureus and physicochemical parameters that will be calculated and determined.

2. Material and Methods

2.1. Experimental Data

Twenty 2-benzylthiopyrimidine derivatives were used to perform this QSAR study. Their IC₅₀ measured on S. aureus range from 6.07 to 125.51 µg/mL [7,8]. To get a good correlation, IC₅₀ was converted into PIC₅₀, by the following relation.

[picture] | (1)

Figure 1 shows the general structure of twenty 2-benzylthiopyrimidine derivatives and Table 1 shows the molecular structures with their corresponding IC₅₀ and PIC₅₀.

Figure 1. General structure of 2-benzylthiopyrimidine derivatives

Table 1. Molecular structures of the twenty 2-benzylthiopyrimidine derivatives and experimental activities of S. aureus

2.2. Theoretical Data

2.2.1. Calculation Software

The free software ChemSketch [21] was used to draw the structure of the compounds and to calculate the physicochemical parameters which are Molar Volume (MV) and the partition coefficient (LogP). The program Gaussian 09 [22], was then used to optimize the geometry of the twenty derivatives structures. The Density Functional Theory (DFT) method, with the B3Lyp functional, associated with the 6-31G(d,p) basis, has been used for this purpose. This allowed the calculation of geometrical parameters including the l(C-S) and the energies of the Highest Occupied Molecular Orbitals (HOMO) and Lowest Unoccupied Molecular Orbitals (LUMO) from which the Ionization Potential (IP) and Electronic Affinity (EA) have been calculated. At last, the Micro Office pro-software XLSTAT 2016 version [23] was used for the model search.

2.2.2. Physicochemical Parameters

In the search for the best model, the five physicochemical parameters that have been chosen were MV, LogP, IP, EA, and l(C-S).

Molar Volume (MV)

MV is a function that takes into account all the conformations of the compound under physiological conditions. It was calculated from the relationship:

[picture] | (2)

MW: Molecular Weight

d: density

The partition coefficient (LogP)

LogP is one of the parameters widely used in QSAR studies in pharmaceutical, biochemical, toxicological, and environmental sciences.

The ionization potential (IP)

IP is the energy that must be supplied to a neutral gaseous atom and isolated in its fundamental state, to take it off the less linked electron.

[picture] | (3)

The Electronic Affinity (EA)

EA is the energy required to oxidize a gaseous anion to the state of a neutral gaseous atom. It is simply the ionization energy of the gaseous anion.

[picture] | (4)

The length of the C-S bond [l (C-S)]

The values of the geometrical parameters such as bonds, valence angles, and dihedral angles have been obtained after an optimization calculation of the molecule. The length of the C-S bond used is illustrated by the Figure 2 below.

Figure 2. Carbon-Sulfur bond length [l(C-S)]

2.3. Criteria for Model Validation

Several methods of calculating correlations exist, but NLMR was chosen in this work. The best QSAR model was selected according to the following statistical criteria: the coefficient of determination (R) and its square (R²), the standard deviation (S), the Fischer coefficient (F), and the cross-correlation coefficient [24,25]. The first three parameters relate to the adjustment of the calculated and experimental values. They transcribe the predictive capacity within the limits of the model, and allow to estimate the precision of the calculated values. The last criteria, , concerns the predictive capacity outside the model and therefore allows us to judge the predictive capacity of the model.

[picture] | (5)

[picture] | (6)

N is the number of compounds in the test series

K is the number of physicochemical parameters

[picture] | (7)

[picture] | (8)

3. Results and Discussion

The antibacterial activity of twenty 2-benzylthiopyrimidine derivatives was predicted on S. aureus strains using physicochemical descriptors such as LogP, MV, IP, EA and l(C-S), respecting the full methodology of a QSAR study and all Organization for Economic Cooperation and Development (OECD) criteria [26]. The results were reported in Table 2 to Table 5.

3.1. QSAR Model

The equation of QSAR model obtained from a NLMR was presented as follows:

[picture] | (9)

The values of physicochemical parameters, experimental and theoretical values of antibacterial activities of the twenty 2-benzylthiopyrimidine derivatives on S. aureus strains were reported in Table 2.

Table 2. Physicochemical parameters and biological activities of the 20 derivatives

Figure 3. Regression line of the model

Figure 4. Similarity between experimental and theoretical antibacterial activities

The similarity between the experimental and theoretical antibacterial activity values for the training and validation sets was represented in Figure 3 and Figure 4.

Figure 4 shows a similar evolution of the experimental and theoretical values of the antibacterial activity of the twenty 2-benzylthiopyrimidine derivatives on a strain of S. aureus using the model.

3.2. Model Validation

The theoretical statistical indicators for validation and the OECD standards were recorded in Table 3.

Table 3. Theoretical statistical indicators for validation and OECD standards

The analysis of Table 3 showed that R² = 0.955. This value, nearly to 1, indicated a strong correlation between the different parameters used and the antibacterial activity of the twenty 2-benzylthiopyrimidine derivatives on the S. aureus strain. The low value of S = 0.091, expressed the small gap between the predicted values and the experimental mean, i.e. the strong predictive power of the model. The significance of the model's parameters was expressed by F; whose value was 37.931. This value could be statistically considered significant as it was high compared to the Fisher table critical value of 2.96 [27]. The value of = 0.952 indicated that our model is excellent because according to Erikson et al [28], when > 0.9, the model was excellent. Moreover, R² - = 0.003 < 0.3, showed that the model was more than acceptable. All these statistical parameters showed that the developed model explains the antibacterial activity of 2-benzylthiopyrimidine derivatives adequately. This result was confirmed by the ratio of theoretical to experimental activities in the validation series in Table 4, which tend towards 1.

Table 4. Ratio between PIC50-Theo and PIC₅₀-Exp

3.3. Contribution of Physicochemical Parameters

The correlation between these parameters and the experimental data was given in Table 5. The results show the partial correlation coefficient was below 0.8, meaning that the parameters were independent two by two.

Table 5. Correlation matrix between the different physicochemical parameters

The contribution of each parameter in the determination of the antibacterial activity of 2-benzylthiopyrimidine derivatives has been showed in Figure 5.

Figure 5 shows that LogP was the best parameter in the determination of PIC₅₀ of 2-benzylthiopyrimidine derivatives. The second and third parameters, respectively, was MV and. IP. l(C-S) and EA do not have a great influence on the PIC₅₀ of 2-benzylthiopyrimidine derivatives.

Figure 5. Contribution of physicochemical parameters

4. Conclusion

The objective of this work was to develop a QSAR model capable to predict the antibacterial activity of a series of twenty 2-benzylthiopyrimidine derivatives, evaluated on a multi-resistant S. aureus strain. Using NLMR, a mathematical relationship was established between PIC₅₀ and the quantum parameters such as LogP, MV, IP, EA, and l(C-S). The statistical indicators of model validation were in agreement with OECD standards (R² = 0.955; S = 0.091; F=37.931 and = 0.952). The QSAR model developed was therefore robust and had good predictive power. The PIC₅₀ predicted by the model was in perfect accordance with the experimental PIC₅₀. In addition, the model used three important parameters in the determination of the PIC₅₀, namely LogP, MV, and IP.

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