## 2 Results and Discussion
### Theoretical Calculations  
The theoretical calculations at the DFT/B3 LYP/311++G(d,p) level for all investigated sulfonamides were carried out in order to characterize the molecular structures and electronic parameters of molecules **8a-m**. In addition, theoretical calculations provided the molecular structures of the analyzed molecules for the molecular docking study. The view of molecules **8a-m** in conformation obtained after energy minimization and geometric parameter optimization with the vector's dipole moment is shown in Figure 1.  
Figure 1: Molecules **8a-m** with the vector’s dipole moment in the low-energy conformation obtained from calculations at the DFT/B3 LYP/6-311++G(d,p) level. The conformation of the common pyrazololotti2,3-_e_[1,2,4]triazine-ethoxybenzene-sulfo namide structural part of the molecules was described by five torsion angles: \(\varphi_{1}\) = N2-C3-C12-C13, \(\varphi_{2}\) = C12-C13-O18-C19, \(\varphi_{3}\) = C13-O18-C19-C20, \(\varphi_{4}\) = C17-C16-S21-N24 and \(\varphi_{5}\) = C16-S21-N24-X (Figure 2). The values of these torsion angles are presented in Table 1.  
The torsion angle \(\varphi_{1}\) shows that the pyrazolotriazine and benzene rings were twisted to each other, adopting the _gauche_ conformation for all molecules. The ethoxy substituent of the benzene ring had _trans-trans_ conformation, as shown by the torsion angles \(\varphi_{2}\) and \(\varphi_{3}\). The sulfonamide part of molecules **8a-m** adopted _gauche-gauche_ conformation, confirmed by torsion angles \(\varphi_{4}\) and \(\varphi_{5}\). It should be noted that in all molecules, a very similar conformation of their common structural part was observed, with greater differentiation being observed in the conformation of the sulfonamide fragment, where the torsion angles \(\varphi_{4}\) and \(\varphi_{5}\) varied within a range of 33\({}^{\circ}\) and 53\({}^{\circ}\), respectively. Moreover, this conformation did not depend on the type of sulfonamide substituent and its chirality. It should be noted that the conformations of **8a-m** obtained from theoretical calculations were similar to that observed in the crystalline state for the structurally similar 3-(1,3-dimethyl-1\(H\)-pyrazolo[4,3-\(e\)][1,2,4]triazin-5-yl)-4-ethoxybenzene-sulfonamide, where the torsion angles \(\varphi_{1}\), \(\varphi_{2}\), \(\varphi_{3}\) and \(\varphi_{4}\) were 38.1(3)\({}^{\circ}\), 172.94(17)\({}^{\circ}\), 178.53(18)\({}^{\circ}\) and \(-\)109.85(19)\({}^{\circ}\), respectively [29]. The electronic parameters theoretically calculated for compounds **8a-m** in the conformation of the molecules obtained in their minimum energy are presented in Table 2.  
For the reactivity and stability descriptors of molecules **8a-m**, the frontier orbitals HOMO and LUMO were used. The energies of the HOMO and LUMO orbitals were very similar for all investigated compounds, changing in the range of 9.124 and 2.253 kcal/mol for E\({}_{\text{HOMO}}\) and E\({}_{\text{LUMO}}\), respectively. It is worth noting that the lowest value of ionization potential of 145.160 kcal/mol and the lowest energy gap \(\Delta E=E_{\text{LUMO}}-E_{\text{HOMO}}\) of 82.304 kcal/mol had a compound **8m**, while for the other compounds, the energy gap varied within a narrow range from 87.355 kcal/mol for **81** to 89.927 kcal/mol for **8a**. The graphical representation of the wave functions of the HOMO and LUMO orbitals for compounds **8a** and **8j**, exhibiting the highest inhibitory activity among the tested compounds on unknown tyrosinase and jack bean urease, respectively, is shown in Figure 3. For both molecules, the HOMO orbital was concentrated practically on the pyrazolo[4,3-\(e\)][1,2,4]triazine-ethoxybenzenesulfonamide system, while the LUMO orbital was distributed on the atoms of the pyrazolo[4,3-\(e\)][1,2,4]triazine ring. A similar distribution of frontier orbitals was observed in the molecules of other compounds.