Prediction of the Antiinflammatory Activity of New S-alkyl Derivatives of 1,2,4-triazol-3-thiones Using the PASS Computer Program and Molecular Docking

The strategy of rational approaches to the search for selective COX-2 inhibitors as potential antiinflammatory agents has been proposed and elaborated. It is based on the use of PASS-prediction and molecular docking. The choice of the basic structure of 4-amino-3-thio-1,2,4triazole as a promising object of chemical modification has been substantiated. Using a modification of the primary molecule, a virtual library of S-derivatives of 5-substituted 4-amino(pyrrol)3-thio-4H1,2,4-triazoles in the amount of 100 compounds (ten groups) has been obtained by introducing various pharmacophore fragments. Based on the analysis of the results of the PASS-prediction and molecular docking, six of the ten planned groups of compounds have been selected for the synthesis as promising selective COX-2 inhibitors. The reliability of the prediction results has already been confirmed for one of the promising group 4-amino-5-(pyridine-4-yl)-1,2,4-triazole (4Н)3-yl-thioacetamides.


INTRODUCTION
The synthesis of new structures with the predicted activity is expedient to carry out in that class of chemical compounds where substances with a certain directed action have been already found (Oliveira et al., 2019).
Scientists refer the heterocyclic system of 1,2,4-triazole to the privileged structure ("privileged scaffold"), since most of the derivatives of this heterocyclic synthesized exhibit some pharmacological activity, including the antiinflammatory (Zhuang et al., 2017). The combination of factors affecting biochemical processes, as well as the practical absence of toxic effects on the body, indicates the feasibility of further targeted search for new biologically active substances among derivatives of 1,2,4-triazole (Mioc et al., 2017). A careful study of the literature data on the spectrum of pharmacological properties of the heterocyclic system of 1,2,4-triazole allows us to confidently assert that the presence of this cycle in the structure of substances determines the manifestation of the antiinflammatory activity (Moise et al., 2009).
In addition, 1,2,4-triazole derivatives are low-toxic, rather simple in synthesis and highly reactive substances. It allows to introduce various pharmacophore fragments into their structure (Khanage et al., 2012). Our analysis of the scientific literature has shown that despite a large number of publications devoted to functional derivatives of 1,2,4-triazole the pharmacological potential of this class of compounds at the present stage is not exhausted.
The compound of 4-amino-3-thio-1,2,4-triazole has a high synthetic potential, significant opportunities in terms of the introduction of pharmacophore fragments and, correspondingly, the expansion of the spectrum for searching the biological activity. The presence of a sulfur atom in the basic structure increases lipophilicity and, therefore, can improve absorption and bioavailability of the compounds synthesized on its basis (Jin et al., 2007).
In addition, thio and amino groups are reaction centers for the introduction of additional pharmacophores into the molecule.
2. Introduction of the arylidene aniline fragment (II) to alkyl derivatives of group (I), it will increase the number of unsaturated bonds in the molecule and may increase the activity. and teratogenicity (Lagunin et al., 2000).
The prediction result is presented in the form of confidence "to be active" -Pa and "to be inactive" -Pi by the types of activity. It should be noted that the data obtained using the PASS program can serve only as an indicative characteristic when selecting promising molecules and help to conduct the primary sample of probable promising groups. It is known that the Pa value reflects, first of all, the similarity of the molecule with the most typical known drugs of the training sample (Assyl et al., 2014).
In order to optimize the targeted search for COX-2 inhibitors as potential antiinflammatory agents and substantiate the feasibility of the experimental screening for the antiinflammatory activity the docking studies were also conducted (Laube et al., 2016). Conducting the docking studies has allowed us to investigate the affinity of a definite group of compounds to this biological target, predict the ability of substances to inhibit the catalytic activity of 1СХ2 and 6СОХ, i.e. to identify their inhibitor, which is a key link in the pathogenesis of the disease. The use of in silico methods also makes it possible to save laboratory animals in the case of complete absence of affinity to potential biological targets (Leelananda & Lindert, 2016).

Method
Generation of the 3D-structure of the planned substances and their optimization using the method of molecular mechanics MM+ and semi-empirical quantum mechanical method PM3 Objects of this study were derivatives of 4-amino-5-

RESULTS AND DISCUSSION
According to the prediction results the probability of  Table I. Visualization of docking results for the most promising compound of group VI is presented in Figure 3. The planned substances have been synthesized and tested for antiinflammatory activity, besides it has also been published scientifically (Chalenko et al., 2019).

CONCLUSION
In order to search for potential antiinflammatory agents 1,2,4-triazol-3-thiones have been selected as promising objects of chemical modification. The strategy of rational approaches to the search for selective COX-2 inhibitors as potential antiinflammatory agents has been proposed and elaborated. It is based on the use of the PASSprediction and molecular docking. Based on the results of the PASS-prediction and molecular docking, six of the ten planned groups of compounds have been selected for the synthesis as promising selective COX-2 inhibitors.