# Assessment of Bioavailability Parameters of Mono- and Bistriazole Derivatives of Propynoylbetulin
## 4 Discussion
The best correlation was obtained for the relationship between experimental lipophilicity, molecular mass (M), and topological polar surface (TPSA) (Equation (5)), for which the correlation cofactor is equal to 0.860. The lipophilicity (logPcalc) values calculated using Equation (5) are presented in Table S1. \[\text{logP}_{\text{calc}}=1.31\text{M}-1.50\text{ TPSA}+1.120 \tag{5}\]  
(r = 0.860; SD = 1.465; VIP = 2.13; \[F=18.45\] ),  
Comparing the lipophilicity obtained by different methods shows that Equation (5) reproduces the experimental lipophilicity better than the theoretical methods. The physicochemical parameters were used to determine the in silico pharmacokinetic properties determining the absorption of the compound [70]. The intestinal mucosa absorption was described using Caco-2 permeability (logPapp) and human intestinal absorption (HIA) [56; 57]. The logPapp values calculated for mono- and bistriazoles are in the range from 0.342 to 0.808 and from 0.001 to 0.605, respectively (Table 4). The tested compounds show moderate Caco-2 permeability, because the logPaap values are lower than 0.9. Most monotriazoles **(3**-**10**) were characterized by better Caco-2 permeability than bistriazoles **(11**-**18**). The higher HIA index shows that most derivatives could be absorbed from the gastrointestinal system into the bloodstream, except from triazole **15** which could be poorly absorbed. The tested derivatives **3**-**18** could be used as transdermal drugs because the calculated logKp for all compounds is lower than \(-2.5\)[55]. The neurotoxicity of com  
Figure 4: The cluster analysis of the experimental and theoretical lipophilicity for compounds **3**–**18**. pounds depends on the passage through the blood-brain barrier and the penetration of the central nervous system (CNS), which was determined by logBB and logPS parameters, respectively [58]. The in silico values of logBB and logPS were determined using pkCSM software [55]. The logBB value for the tested compounds is in the range from \(-2.220\) to \(-0.522\), which means that triazole was poorly distributed to the brain (Table 4). Comparing the logBB parameter of mono- (**3-10**) and bistriazoles (**11-18**) shows that the introduction of triazole substituent at C3 position of betulin scaffold reduces passage through blood-brain barrier. Most monotriazoles could penetrate the central nervous system because the logPS value is higher than \(-3\), except for triazoles with a sugar moiety (**7** and **8**), which were unable to penetrate the central nervous system. In the series of bistriazoles (**11-18**), only compounds with a phenyl substituent in the triazole moiety (**11-14**) could penetrate the CNS. Based on the obtained results, it can be concluded that the introduction of a phenyl substituent to the triazole ring increases the neurotoxicity of the obtained compounds. The ADME in silico-determined parameters were compared with the experimental lipophilicity (logP\({}_{\text{TILC}}\)) using similarity analysis (Figure 5). As seen on Figure 5, compounds are localized in two main clusters. The first cluster includes bistriazoles with a sugar moiety (**15-16**). The second cluster is divided into three subclusters which contain bistriazoles **11-14**, compounds **7-8** and **17-18**, and monotriazoles **3-6** and **9-10**, respectively. The analysis of the Euclidean distance between subclusters shows that the type of substituent at the triazole ring influences the ADME (adsorption, distribution, metabolite, and extraction) properties, while the number of triazole rings slightly affects the bioavailability properties of the compound.