Synthesis, Single Crystal X-Ray Analysis, Prediction and Study of Pharmacological Activity of 4-(1H-Benzo[d]imidazol-2-yl)-1-Phenyl-1H-1,2,3-triazol-5-Amine and Its Solvates

A method for the synthesis of 4- (1H-benzo[d]imidazole-2-yl)-1-phenyl-1H-1,2,3-triazole-5-amine was developed, and the electronic and spatial structure of this molecule was studied theoretically and experimentally. The study of interaction energies between molecules by quantum-chemical calculations allows us to recognize different levels of crystal structure organization and describe the interaction types causing their formation. The classic N-H…N and C-H…N hydrogen bonds play the main role in all the studied crystals forming the primary basic structural motif. Their role is comparable with the role of the stacking interactions. The molecular docking study predicted that the studied compound may exhibit anti-hepatitis B activity, and experimental in vitro studies confirmed that it is a potent HBV inhibitor with IC50 in a low micromolar range.

One of the promising areas of pharmaceutical chemistry is the creation of dipharmacophore substances incorporating molecular groups of various therapeutic orientations. This approach allows us to design new biologically active substances that have innovative potentials. A number of papers describe dipharmacophore molecules containing in their structures covalently linked 1,2,3-triazolide and benzimidazole moieties [22][23][24].
In the present work, using 4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-1,2,3-triazol-5-amine as an example, we developed a one-step method for the synthesis of benzimidazole -1,2,3-triazole hybrid molecules. We studied its electronic and crystal structure using spectral methods and X-ray diffraction analysis. Based on the results of 3D pharmacophore screening, we also evaluated the potential pharmacological activity of this molecule as well as its solvated forms.
In the present work, using 4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-1,2,3-triazol-5-amine as an example, we developed a one-step method for the synthesis of benzimidazole -1,2,3-triazole hybrid molecules. We studied its electronic and crystal structure using spectral methods and X-ray diffraction analysis. Based on the results of 3D pharmacophore screening, we also evaluated the potential pharmacological activity of this molecule as well as its solvated forms.

Molecular and Crystal Structure Analysis
The structures of compounds 3, 3a and 3b were studied using different spectral methods (see Materials and Methods section, and Supplementary Materials) and finally confirmed using the single crystal X-ray diffraction analysis.
The crystallographic information and refinement data are presented in the Materials and Methods Section.
The compounds 3a and 3b have been obtained as solvates with THF and pyridine, respectively, at the stoichiometric ratio 1:1. The asymmetric part of the unit cell of the studied crystals contains one molecule of the title compounds ( Figure 2). The bond lengths are very similar in all basic molecules of the title compounds (Table S1). The nitrogen atom of the amino group has a pyramidal configuration with different degrees of pyramidality in compounds 3, 3a and 3b ( Table 1). The highest degree of pyramidality is observed in crystal 3, while the nitrogen atoms of amino group in crystals 3a and 3b have a smaller degree of pyramidality. This reflects considerable conjugation between the π-system of the triazole ring and the N6 atom lone pair which is confirmed by the shorter length of the C9-N6 bond (Table 1). It is caused by full involvement of two hydrogen atoms of amino group in formation of both intramolecular N6-H6NB . . . N1 and intermolecular hydrogen bonds with solvent molecules ( Table 2). The phenyl substituent is turned relative to the C9-N5 endocyclic bond (the C9-N5-C10-C15 torsion angles are shown in Table 1 The structures of compounds 3, 3a and 3b were studied using different spectral methods (see Materials and Methods section, and Supplementary Materials) and finally confirmed using the single crystal X-ray diffraction analysis.
The crystallographic information and refinement data are presented in the Materials and Methods Section.
The compounds 3a and 3b have been obtained as solvates with THF and pyridine, respectively, at the stoichiometric ratio 1:1. The asymmetric part of the unit cell of the studied crystals contains one molecule of the title compounds ( Figure 2). The bond lengths are very similar in all basic molecules of the title compounds (Table S1). The nitrogen atom of the amino group has a pyramidal configuration with different degrees of pyramidality in compounds 3, 3a and 3b ( Table 1). The highest degree of pyramidality is observed in crystal 3, while the nitrogen atoms of amino group in crystals 3a and 3b have a smaller degree of pyramidality. This reflects considerable conjugation between the π-system of the triazole ring and the N6 atom lone pair which is confirmed by the shorter length of the C9-N6 bond ( Table 1). It is caused by full involvement of two hydrogen atoms of amino group in formation of both intramolecular N6-H6NB…N1 and intermolecular hydrogen bonds with solvent molecules ( Table 2). The phenyl substituent is turned relative to the C9-N5 endocyclic bond (the C9-N5-С10-C15 torsion angles are shown in Table 1   The organic molecules such as the studied compound 3 have the ability to form solvates with different molecules which contain strong enough proton acceptors. Therefore, special attention should be paid to the intermolecular interactions and their role in the crystal structure formation.  The organic molecules such as the studied compound 3 have the ability to form solvates with different molecules which contain strong enough proton acceptors. Therefore, special attention should be paid to the intermolecular interactions and their role in the crystal structure formation. In the crystals 3a and 3b, cavities that contain solvent molecules are formed. The cavities have a volume of 487.52 Å 3 in compound 3a and 471.76 Å 3 in compound 3b, which account for 28% and 27% of their unit cell size, respectively. They are formed along the a crystallographic axis (Figure 3). In the crystals 3a and 3b, cavities that contain solvent molecules are formed. The cavities have a volume of 487.52 Å 3 in compound 3a and 471.76 Å 3 in compound 3b, which account for 28% and 27% of their unit cell size, respectively. They are formed along the a crystallographic axis (Figure 3). Modern crystal engineering is based on various approaches to the crystal structure analysis, including the close packing principles of Kitaigorodskii [27], the Popelier's principles [28], the set of graphs applied to the crystal structure analysis [29], the Etter's rules [30], or the Desiraju's concept of supramolecular synthons [31][32][33]. All these approaches are based mainly on the study and geometric parameters comparison of intermolecular interactions. The modern basic method is the concept of supramolecular synthons, which allows us to describe a crystal as a packing of molecular assemblies bound by any specific intermolecular interactions (hydrogen or halogen bonds, stacking interaction, etc [31][32][33]). This concept turned out to be very useful and has made significant progress in studying and predicting the crystal structure [32]. Nevertheless, the release of the basic supramolecular synthon is reliable in the presence of only one strong intermolecular interaction. This task becomes very equivocal in the presence of two or more strong hydrogen bonds, or weak interactions with close geometric parameters, or when specific intermolecular interactions are absent at all. For example, as shown earlier, the application of the geometric approach has proved to be unsuccessful in determining the strongest intermolecular interaction in crystals of diaminobenzenes and nitro-diaminobenzenes [34,35].
The analysis of interatomic distances in crystal 3 indicates the presence of a set of intermolecular C-H…X H-bonds, one N-H…N hydrogen bond and stacking interaction with a "head-to-head" orientation ( Table 2). Based on their geometrical parameters, it is possible to suggest that all of these interactions are weak, except for N2-H2N…N3' H-bond (Table 2). Іn crystals 3a and 3b, the number of C-H...X interactions is reduced (Table 3). Іn these crystals, the set of intermolecular interactions is almost identical. Іt should be noted that the N2-H2N…N3' hydrogen bond and the hydrogen bond formed between the amino group and the solvate molecule are also stronger than others (Table 3). Visual analysis of crystal structures 3, 3a and 3b allows us to recognize the centrosymmetric dimers bound by the N2-H2N…N3' and C5-H5…N4' hydrogen bonds ( Figure 4, Table 2; Table 3). These dimers are packed in the layers due to the stacking interactions ( Figure 5). Ergo, routine analysis of specific intermolecular interactions in the crystal does not allow us to make definite conclusions about the preferred packing arrangement of molecules and the role of weak hydrogen bonds. This may be done only on the basis of consideration of topology of interactions between molecules in terms of their directionality and energies.

Іnteraction
Operation of Symmetry H…A, Å D-H…A, Modern crystal engineering is based on various approaches to the crystal structure analysis, including the close packing principles of Kitaigorodskii [27], the Popelier's principles [28], the set of graphs applied to the crystal structure analysis [29], the Etter's rules [30], or the Desiraju's concept of supramolecular synthons [31][32][33]. All these approaches are based mainly on the study and geometric parameters comparison of intermolecular interactions. The modern basic method is the concept of supramolecular synthons, which allows us to describe a crystal as a packing of molecular assemblies bound by any specific intermolecular interactions (hydrogen or halogen bonds, stacking interaction, etc. [31][32][33]). This concept turned out to be very useful and has made significant progress in studying and predicting the crystal structure [32]. Nevertheless, the release of the basic supramolecular synthon is reliable in the presence of only one strong intermolecular interaction. This task becomes very equivocal in the presence of two or more strong hydrogen bonds, or weak interactions with close geometric parameters, or when specific intermolecular interactions are absent at all. For example, as shown earlier, the application of the geometric approach has proved to be unsuccessful in determining the strongest intermolecular interaction in crystals of diaminobenzenes and nitro-diaminobenzenes [34,35].
The analysis of interatomic distances in crystal 3 indicates the presence of a set of intermolecular C-H . . . X H-bonds, one N-H . . . N hydrogen bond and stacking interaction with a "head-to-head" orientation ( Table 2). Based on their geometrical parameters, it is possible to suggest that all of these interactions are weak, except for N2-H2N . . . N3 H-bond (Table 2). In crystals 3a and 3b, the number of C-H...X interactions is reduced (Table 3). In these crystals, the set of intermolecular interactions is almost identical. It should be noted that the N2-H2N . . . N3 hydrogen bond and the hydrogen bond formed between the amino group and the solvate molecule are also stronger than others (Table 3). Visual analysis of crystal structures 3, 3a and 3b allows us to recognize the centrosymmetric dimers bound by the N2-H2N . . . N3 and C5-H5 . . . N4 hydrogen bonds ( Figure 4, Tables 2 and 3). These dimers are packed in the layers due to the stacking interactions ( Figure 5). Ergo, routine analysis of specific intermolecular interactions in the crystal does not allow us to make definite conclusions about the preferred packing arrangement of molecules and the role of weak hydrogen bonds. This may be done only on the basis of consideration of topology of interactions between molecules in terms of their directionality and energies.  Table 3. Intermolecular interactions in 3a and 3b crystals.

Interaction
Operation of Symmetry 3a 3b    Іn terms of the energy of interactions between molecules, the study of the crystal structure was carried out using the method described previously [36,37] (calculation procedure is presented in detail in the Materials and Methods Section). This method does not depend on the nature of specific intermolecular interactions and their geometric parameters and takes into account all possible types of the intermolecular interactions. The first coordination sphere for each of the molecules located in the asymmetric part of the unit cell contains 16-27 molecules in the crystals of compounds 3, 3a and 3b. Data for dimers with interaction energies higher than 1% of the total interaction energy of the basic molecule with all the molecules belonging to its first coordination sphere are given in Table 4  Table 5 Table 6. Table 4. Symmetry codes, bonding type, interaction energy of the basic molecule with neighboring ones (Eint, kcal/mol) with the highest values (more than 1 % of the total interaction energy) and the contribution of this energy to the total interaction energy (%) in crystals of 3.

Dimer
Symmetry The analysis of pairwise interaction energies in the crystal of 3 has revealed that the first coordination sphere of the basic molecule contains 16 neighboring molecules. The calculations of the pairwise interaction energies of the basic molecule with each of its neighbors have revealed one In terms of the energy of interactions between molecules, the study of the crystal structure was carried out using the method described previously [36,37] (calculation procedure is presented in detail in the Materials and Methods Section). This method does not depend on the nature of specific intermolecular interactions and their geometric parameters and takes into account all possible types of the intermolecular interactions. The first coordination sphere for each of the molecules located in the asymmetric part of the unit cell contains 16-27 molecules in the crystals of compounds 3, 3a and 3b. Data for dimers with interaction energies higher than 1% of the total interaction energy of the basic molecule with all the molecules belonging to its first coordination sphere are given in Tables 4-6. Table 4. Symmetry codes, bonding type, interaction energy of the basic molecule with neighboring ones (E int , kcal/mol) with the highest values (more than 1 % of the total interaction energy) and the contribution of this energy to the total interaction energy (%) in crystals of 3.

Dimer
Symmetry   (Table 4). As a result, the double column (Figure 7) can be recognized as the primary basic structural motif (BSM1) in the crystal of 3. The interaction energy of each molecule with its neighbors within the column is −53.54 kcal/mol. The molecules belonging to the neighboring columns are bound by the C-H . . . π and N-H . . . N hydrogen bonds. The interaction energies of the primary BSM with neighboring columns are anisotropic enough. It allows to separate out the layer parallel to the (−1 0 1) crystallographic plane as the second basic structural motif (BSM2) (Figure 7) where the interaction energy between neighboring layers is almost ten times smaller than the interaction energy within the layer (−72.10 kcal/mol). The neighboring layers are bound by the C-H . . . π hydrogen bonds and non-specific interactions. Therefore, we can conclude that crystal 3 has two levels of organization and can be classified as columnar-layered.  Table 4). The strongest bonded dimer 3-d12 ( Figure  6) is formed due to classic N-H…N and C-H…N hydrogen bonds, while the molecules within two other strongly bonded dimers 3-d1 and 3-d2 are linked by the stacking interaction with the "head to head" orientation ( Table 4). As a result, the double column (Figure 7) can be recognized as the primary basic structural motif (BSM1) in the crystal of 3. The interaction energy of each molecule with its neighbors within the column is -53.54 kcal/mol. The molecules belonging to the neighboring columns are bound by the C-H…π and N-H…N hydrogen bonds. The interaction energies of the primary BSM with neighboring columns are anisotropic enough. Іt allows to separate out the layer parallel to the (−1 0 1) crystallographic plane as the second basic structural motif (BSM2) (Figure 7) where the interaction energy between neighboring layers is almost ten times smaller than the interaction energy within the layer (-72.10 kcal/mol). The neighboring layers are bound by the C-H…π hydrogen bonds and non-specific interactions. Therefore, we can conclude that crystal 3 has two levels of organization and can be classified as columnar-layered.  The introduction of the solvent molecule into the crystal causes some change in the crystal organization. The analysis of pairwise interaction energies has revealed that the first coordination sphere of the basic molecule 3 contains 16 neighboring molecules in both solvates while the solvate molecule is surrounded by 11 neighboring molecules in crystal 3a and 9 neighboring molecules in crystal 3b ( Table 5; Table 6). Similar to crystal 3, the most strongly bound dimer 3a-d8 and 3b-d8 is formed due to classic N-H…N and C-H…N hydrogen bonds, while the molecules within another strongly bound dimer 3a-d7 and 3b-d7 are linked by the stacking interaction with "head to tail"  Table 4). The strongest bonded dimer 3-d12 ( Figure  6) is formed due to classic N-H…N and C-H…N hydrogen bonds, while the molecules within two other strongly bonded dimers 3-d1 and 3-d2 are linked by the stacking interaction with the "head to head" orientation ( Table 4). As a result, the double column (Figure 7) can be recognized as the primary basic structural motif (BSM1) in the crystal of 3. The interaction energy of each molecule with its neighbors within the column is -53.54 kcal/mol. The molecules belonging to the neighboring columns are bound by the C-H…π and N-H…N hydrogen bonds. The interaction energies of the primary BSM with neighboring columns are anisotropic enough. Іt allows to separate out the layer parallel to the (−1 0 1) crystallographic plane as the second basic structural motif (BSM2) (Figure 7) where the interaction energy between neighboring layers is almost ten times smaller than the interaction energy within the layer (-72.10 kcal/mol). The neighboring layers are bound by the C-H…π hydrogen bonds and non-specific interactions. Therefore, we can conclude that crystal 3 has two levels of organization and can be classified as columnar-layered.  The introduction of the solvent molecule into the crystal causes some change in the crystal organization. The analysis of pairwise interaction energies has revealed that the first coordination sphere of the basic molecule 3 contains 16 neighboring molecules in both solvates while the solvate molecule is surrounded by 11 neighboring molecules in crystal 3a and 9 neighboring molecules in crystal 3b ( Table 5; Table 6). Similar to crystal 3, the most strongly bound dimer 3a-d8 and 3b-d8 is formed due to classic N-H…N and C-H…N hydrogen bonds, while the molecules within another strongly bound dimer 3a-d7 and 3b-d7 are linked by the stacking interaction with "head to tail" The introduction of the solvent molecule into the crystal causes some change in the crystal organization. The analysis of pairwise interaction energies has revealed that the first coordination sphere of the basic molecule 3 contains 16 neighboring molecules in both solvates while the solvate molecule is surrounded by 11 neighboring molecules in crystal 3a and 9 neighboring molecules in crystal 3b (Tables 5 and 6). Similar to crystal 3, the most strongly bound dimer 3a-d8 and 3b-d8 is formed due to classic N-H . . . N and C-H . . . N hydrogen bonds, while the molecules within another strongly bound dimer 3a-d7 and 3b-d7 are linked by the stacking interaction with "head to tail" orientation (Tables 5 and 6). As a result, the zig-zag columns can be recognized as the primary basic structural motif (BSM1) in crystals 3a and 3b (Figure 8). The molecules within the columns are also bound by two strongest interactions, and the interaction energies of the basic molecule with its neighbors within the column are −42.15 kcal/mol (3a) and −40. with neighboring columns are almost isotropic because of the interaction energies vary in the range of −4.24 ÷ −9.22 kcal/mol (3a) and −6.10 ÷ −9.33 kcal/mol (3b) (Figure 8). The interaction energy between the neighboring columns is several times smaller than the interaction energy within the column. Thus we can conclude that the crystals 3a and 3b have only one level of organization and can be classified as columnar. It should be noted that despite different solvent molecules in crystals 3a and 3b, their crystal packings are almost isostructural (Figure 8). Table 5. Symmetry codes, bonding type, and interaction energy of the basic molecule with neighboring ones (E int , kcal/mol) with the highest values (more than 1% of the total interaction energy) and the contribution of this energy to the total interaction energy (%) in crystal 3a.

Dimer
Symmetry Operation Non-specific 3b-d20 The comparison of the results of the crystal structure analysis performed by two ways shows clearly that the geometrical characteristics of intermolecular interactions are not informative enough to separate out the main structural motif and study the comparative role of different types of interactions. At the same time, the study of interaction energies between molecules allows us to recognize different levels of crystal structure organization and describe the interaction types causing their formation. Thus, the classic N-H . . . N and C-H . . . N hydrogen bonds play the main role in all the studied crystals forming the primary basic structural motif. Their role is comparable with the role of the stacking interactions. The inclusion of the solvent molecules in the crystals 3a and 3b lead to a more isotropic packing type.

Molecular Docking Simulations
The title molecule was tested as a potential agent capable of interacting with capsid of hepatitis B virus (HBV) and thus inhibit its replication [38][39][40]. The title molecule has been tested as a potential analogue of ligands of protein complexes 5E0I, 5T2P, 5WRE, and 5GMZ. The X-ray crystallographic structures of such ligand-protein complexes are known from [40].
The pharmacophore model and docking procedure were performed by using computer the program complex Ligandscout 4.3 [41]. All the above-mentioned protein structures contain six chains (A, B, C, D, E, and F). According to our preliminary calculations, the residual mean square deviations (RMSD) between docking-generated poses for reference molecule and poses obtained from x-ray data were minimal (RMSD < 1 Å) for D-chains. Therefore, D-site was selected for in silico modeling as the site of the ligand-protein interactions. The LigandScout option was used for pharmacophore generation, and then the title molecule was docked at D-site. The obtained data for score functions are presented in Table 7 (for the description of estimated parameters, see the LigandScout manual). One can see that the title molecule has significant interactions with the corresponding proteins. To illustrate, two receptor-ligand complexes (with 5GMZ and 5T2P) are shown in Figure 9.
The pharmacophore model and docking procedure were performed by using computer the program complex Ligandscout 4.3 [41]. All the above-mentioned protein structures contain six chains (A, B, C, D, E, and F). According to our preliminary calculations, the residual mean square deviations (RMSD) between docking-generated poses for reference molecule and poses obtained from x-ray data were minimal (RMSD < 1 Å) for D-chains. Therefore, D-site was selected for in silico modeling as the site of the ligand-protein interactions. The LigandScout option was used for pharmacophore generation, and then the title molecule was docked at D-site. The obtained data for score functions are presented in Table 7 (for the description of estimated parameters, see the LigandScout manual). One can see that the title molecule has significant interactions with the corresponding proteins. To illustrate, two receptor-ligand complexes (with 5GMZ and 5T2P) are shown in Figure 9.
Іn the 2D pictures in Figure 8, the hydrogen bond acceptor is designated by the red dotted line, and the hydrophobic interaction is designated by the curved yellow line. Іt should also be noted that in the two presented examples, different tautomeric forms of the studied molecule generated by docking procedure form stable ligand-protein complexes.

Anti-Hepatitis B Virus (HBV) Activity
The biological activity of compound 3 was studied using an experimental in vitro hepatitis B virus infection model based on human hepatoma line HepG2 stably transfected with the NTCP gene [42]. This model, which maintains a full virus replication cycle, was developed in our laboratories for identification of viral entry inhibitors, promising candidates to prevent development of resistant HBV forms [43]. The title molecule 3 demonstrated 86% inhibition of HBV replication (in 10 µM concentration) in this model. Taking into account the recently reported test results for viral entry inhibition of FDA approved drugs zafirlukast (ІC50 6.5 µM), TRІAC (ІC50 6.9 µM), and sulfasalazine (ІC50 9.6 µM) [44], compound 3 can be considered as a promising starting point for the development of potent viral entry inhibitors capable to prevent development of resistant HBV forms. In the 2D pictures in Figure 8, the hydrogen bond acceptor is designated by the red dotted line, and the hydrophobic interaction is designated by the curved yellow line. It should also be noted that in the two presented examples, different tautomeric forms of the studied molecule generated by docking procedure form stable ligand-protein complexes.

Anti-Hepatitis B Virus (HBV) Activity
The biological activity of compound 3 was studied using an experimental in vitro hepatitis B virus infection model based on human hepatoma line HepG2 stably transfected with the NTCP gene [42]. This model, which maintains a full virus replication cycle, was developed in our laboratories for identification of viral entry inhibitors, promising candidates to prevent development of resistant HBV forms [43]. The title molecule 3 demonstrated 86% inhibition of HBV replication (in 10 µM concentration) in this model. Taking into account the recently reported test results for viral entry inhibition of FDA approved drugs zafirlukast (IC 50 6.5 µM), TRIAC (IC 50 6.9 µM), and sulfasalazine (IC 50 9.6 µM) [44], compound 3 can be considered as a promising starting point for the development of potent viral entry inhibitors capable to prevent development of resistant HBV forms.

General Information
All chemicals were obtained from Sigma-Aldrich or Merck. All NMR spectra were recorded on a Varian MR-400 spectrometer (Varian, Inc., Walnut Creek, CA, USA) with standard pulse sequences operating at 400 MHz for 1H NMR and 100 MHz for 13C NMR. For NMR spectra, DMSO-d6 was used as solvent. Liquid chromatography mass spectrometry was developed by means of chromatography with PHENOMENEX GEMINI NX C18 110 Further crystallization by slow evaporation of a solution of 3 in acetonitrile was carried out to provide single stick-like colorless crystals suitable for X-ray diffraction analysis. Compounds 3a and 3b were obtained by recrystallization of 3 from THF and pyridine, respectively.

Theoretical Calculations
Analysis of the 3, 3a and 3b crystal structures was performed using an approach based on the calculations of the energies of pair interactions between molecules in a crystal [36,37]. The first coordination sphere of the basic M0 molecule was constructed using the standard procedure in Mercury program (version 4.0, Cambridge, UK) [46]. This procedure was applied individually to each molecule found in the asymmetric part of the unit cell. The observed cluster was taken from X-ray diffraction data and was divided on the dimers in which one molecule M0 is the basic molecule and the second molecule Mi is one of the molecules of its first coordination sphere. The positions of the hydrogen atoms were normalized to 1.089 Å for C-H and 1.015 Å for N-H bonds taking into account the geometry optimization results of isolated molecules. The need for such a procedure is due to the fact that the X-H bonds determined by the X-ray structural study are reduced due to the peculiarities of the method [47]. The energies of pairwise interactions were calculated using the density functional method B97-D3 with Def2-TZVP basis set (B97-D3/ Def2-TZVP) and were adjusted for the BSSE correction [48]. The B97-D3 functional has been evaluated as one of the most reliable dispersion-corrected functional for the calculation of intermolecular interactions [49,50]. The calculations were performed using ORCA software (Max Plank Institute for Chemical Energy Conversion, Version 3.0.3, Ruhr, Germany) [51].
The analysis of the obtained data is based on the assumption that the values of the interaction energies can take on vector properties, since them originate in the geometric center of the basic molecule, and each of them is directed to the geometric center of one of the adjacent molecules [35]. Each length of such an energy vector is normalized to the strongest energy of pairwise interaction by the equation: where R i is the distance between the geometric centers of the interacting molecules, E i is the interaction energy between the two molecules, and E str is the energy of the strongest pair interaction in the crystal. The purpose of such normalization is to make the length of the vector almost independent of the method of calculation. Replacing a molecule with its vector image and applying symmetry operations make it possible to construct an energy vector diagram (EVD) of a molecule and to study the energy structure instead of the large number of intermolecular interactions.

Docking Studies
The pharmacophore model generation and docking were performed using Ligandscout 4.3 program [41].

Conclusions
A new representative of "benzimidazole-1,2,3-triazole" dual moiety molecules, 4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-1,2,3-triazol-5-amine (3), and its solvates with THF (3a) and pyridine (3b) have been synthesized and studied using both theoretical and experimental methods. The studied compounds were characterized by spectral methods, and their molecular and crystal structures were confirmed by X-ray diffraction study. Quantum-chemical calculations were used to study the energies of interactions between molecules to recognize different levels of crystal structure organization and describe the interaction types causing their formation. Analysis of topology of intermolecular interactions in terms of their energy and directionality indicated columnar-layered structure of the crystal 3. The inclusion of the solvent molecules in the crystals 3a and 3b led to more isotropic packing type which could be classified as columnar. The ligand-receptor interactions between compound 3 and its potential hepatitis B viral targets were modeled using the molecular docking approach. At the final stage of this work, experimental in vitro biological studies confirmed that compound 3 is a potent HBV replication inhibitor with IC 50 in a low micromolar range. The comparative literature data demonstrated that the described chemotype could be considered as a promising starting point for the development of anti-HBV drugs capable of preventing development of resistant viral forms.

Funding
The work was supported by Ministry of Science and Higher Education of the Russian Federation in frames of Agreement on reimbursement of costs associated with Development of a platform for biologically active compound libraries design for actual biotargets, including the platform testing on the example of invention and preparation of candidate libraries for HBV treatment designed as inhibitors of viral penetration and assembly of viral core particles (RFMEFI57917X0154).

Conflicts of Interest:
The authors declare no conflict of interest.