## 2 Results and Discussion
### In Silico ADMET Profile  
The use of in silico methods to provide data on the pharmacokinetics and toxicity of hit compounds is an attractive and cost-effective alternative to support decision making in drug development programs for leishmaniasis. Therefore, the curcuminoids and turmerone (**1-6**) were submitted to pharmacokinetic and toxicological profile evaluations  
Figure 3: Binding mode of turmerones with _Li_ARG obtained by molecular docking. The superposition of the final docking pose of each inhibitor docked into the active site of _Li_ARG is shown in the center. The three-dimensional model of _Li_ARG is displayed in cartoon representation and colored green. The molecular structures of (**a**) ar-turmerone (**4**) (grey), (**c**) a-turmerone (**5**) (purple), and (**e**) \(\beta\)-turmerone (**6**) (orange) are shown in stick representation. Residues that participate in interactions are colored in light green. The 2D diagrams show the interactions between (**b**) **4**, (**d**) **5**, and (**f**) **6**.  
using Quantitative Structure-Activity Relationship (QSAR)-based models implemented in VEGA v.1.2.3 and ADMET Predictor (tm) v11.0 (Simulation Plus, Lancaster, CA, USA) softwares. The pharmacokinetic parameters evaluated included oral bioavailability, as determined by the Lipinski rule, the percentage of unbound substance in the plasma, and the likelihood of being a P-glycoprotein (Pgp) substrate (Table 2).  
The results presented herein suggested that these substances exhibit good oral bioavailability after passive oral absorption based on physicochemical properties and low fraction unbound to plasma protein, ranging between 6.2 and 12.1% freedom in the plasma. These are the fractions that will be able to permeate cell membranes, interact with the target protein, and be metabolized. Although this feature may directly impact pharmacodynamics, it may contribute to a longer half-life for these substances [40]. Studies have shown that **1** stability is improved by the main plasma proteins such as human serum albumin (HSA) and fibrinogen [41]. Molecular docking analyses demonstrated that **1** interacts with HSA through the carbonyl oxygen and hydroxyl oxygen of one phenolate [42], these functional groups are also present in the structures of **2** and **3**. HSA is a positively charged protein and has hydrophobic pockets, and then acidic and neutral drugs, respectively, can selectively bind to the protein, resulting in a low unbound fraction in the plasma [43].  
Considering the P-glycoprotein interaction, all the compounds, with the exception of **4**, were substrates and inhibitors of the transporter. [PERSON] and co-workers' (2004) studies suggested that the curcuminoids **1**-**3** bind to substrate-binding sites on Pgp and inhibit the transporter but are not substrates [44]. However, the study by [PERSON] and co-workers demonstrated that in the presence of turmerones **4** and **5**, **1** efflux is reduced. Additionally, the authors showed that only **5** is a Pgp inhibitor since it was able to affect the uptake of rhodamine-123 and digoxin, known Pgp substrates. The results indicated that **1** uptake was increased because of Pgp inhibition by **5**[45]. No related study was found for **6**. Then, all together these results contribute to confirm the in silico prediction and solve the influence of **6** on Pgp activity.