## 3 Results and Discussion
### Cheminformatics Prediction
#### 3.2.4. ADMET Prediction  
The ADMET properties of the compounds **(5-7) _anti_, (5-7) _syn_, and the reference drug marotiline **9**, were predicted using ADMETlab server and the Data Warrior program, and the results were recorded in Tables 6 and 7. In term of absorption, all compounds **(5-7) _anti_** and **(5-7) _syn_** were found to have better membrane permeability (Caco-2) than reference drug **9**. The permeability glycoprotein (P-gp) is the most controlling drug efflux transporter; it shuttles drugs outside the cells, to the gut lumen, to urine from kidney, and outside the brain. The predicting efflux values reveal that all of the tested compounds, which are considered as antidepressants, are passing the central nervous system (CNS) drug efflux problem that leads to decrease their bioavailability. In more detail; the compounds **5 _anti_**, **7 _anti_**, and **7 _syn_** are neither substrates nor inhibitors for P-gp, while the compounds **5 _syn_**, **6 _anti_**, and **6 _syn_** are inhibitors, but not substrates that may help as synergic drugs. On the other hand, the reference drug **9** is inhibitor and substrate. Interestingly, the compounds **6 _anti_** and **6 _syn_** had greater probability as P-gp inhibitors than reference drug **9** (0.814, 0.839, and 0.558, respectively). The Human Intestinal Absorption (HIA) scores are coming in the line of qualitative gastrointestinal (GI) absorption descriptors, as predicted by SwissADME server, that the HIA scores of compounds **7 _anti_** and **7 _syn_** are less than the reference drug **9** score. In terms of distribution, three descriptors were measured; Plasma Protein Binding (PPB), Volume Distribution (VD), and Blood-Brain Barrier (BBB). In fact, there are three types of plasma protein that bind with drugs; human serum albumin, \(\alpha\)- acid glycoprotein, and lipoprotein. The **6 _anti_** is the most one bound to the plasma protein followed by its isomer **6 _syn_** (PPP%: 93.528 and 93.448 respectively; versus, 87.029 of reference drug **9**), that is may refer to their acetoxy group (OCOCH\({}_{3}\)) that increase their topological polar surface area (TPSA). In the same trend, the volume distribution (VD) results predict that compounds **6 _anti_**, and **6 _syn_** are the most confined to blood components (VD: \(-\)0.331 and \(-\)0.323; respectively; versus, 1.603 of reference drug **9**), as well, the isomers **7 _anti_** and **7 _syn_** are strongly confined to blood. On the other hand, the isomers **5 _anti_** and **5 _syn_** were found to evenly distributed between blood and tissue components (VD: 0.581 and 0.604, respectively). All of the compounds could be penetrated through BBB. The **6 _anti_** and **6 _syn_** have the least BBB values (BBB: 0.915 for both; versus 0.984 for reference drug **9**). It is clear that acetoxy group (OCOCH\({}_{3}\)) of the **6 _anti_** and **6 _syn_** raise up their TPSA and could participate in the hydrogen bonding that ultimately lead to decrease their penetration through BBB. This is in a good agreement with the [PERSON] et al. study where the excessive hydrogen bonding restricted the antihistamines penetration into the CNS [65]. In terms of metabolism, the compounds **(5-7) _anti_** and **(5-7) _syn_** could be metabolized by P450 CYP1A2 enzyme, so the lower affinity drugs to this enzyme are not preferred to intake with these compounds, as well, these compounds are not preferred to intake with reference drug **9**, since it has the highest affinity. In addition, only the **5 _anti_** and its isomer **5 _syn_** could behave as reversible and/or irreversible inhibitors for the P450 CYP1A2 enzyme and, thus, lead to reduce and/or diminish its activity. In the same manner, the compounds **(5-7) _anti_** and **(5-7) _syn_** could be metabolized by P450 CYP4, the enzyme responsible for biotransformation for about 30% of prescribed drugs [66]. The reference drug **9** could behave either as substrate or inhibitor for P450 CYP74 enzyme.