2.1.5. ADMET Profiling Study

Sorafenib was used as a reference molecule, as the ADMET variables were investigated for compound **7** with Discovery studio 4.0 software. Both compound **7** and sorafenib showed remarkable similarities according to the ADMET results (Figure 14), showing a very low potential to pass the BBB, and good levels of intestinal absorption in addition to low and very low aqueous solubility levels, respectively. Similarly, both molecules presented a non-inhibitory potential against the cytochrome P-450 and CYP2D6, and revealed more than 90% binding percentage with plasma protein.

**Figure 14.** Computational prediction of ADMET parameters for compound **7** and sorafenib.

2.1.6. In Silico Toxicity Studies

In the presented study, five parameters of toxicity were estimated computationally, in accordance with the toxicity models built in the Discovery studio software. The employed models are; the rat-female FDA rodent carcinogenicity (RF-FDA-C) that predicts if the examined compound is carcinogenic or not, carcinogenic potency TD50 in a mouse model (TD50-M), maximum tolerated dose in rats (MD-R), rat oral LD50 (R-O- LD50), and rat chronic LOAEL (LOAEL-C), in addition to skin and eye irritancy. Table 3 demonstrates the expected general safety of compound **7** against sorafenib.


**Table 3.** In silico toxicity studies of compound **7** and reference molecule.

2.1.7. Molecular Similarity

Similarity Check Using Physical Properties

A molecular similarity study using Discovery studio software was conducted to check the structural similarity between the synthesized compound and the FDA-approved 1*H*inole derivatives (sunitinib **II**, vorolanib **III**, nintedanib **IV**, and toceranib **V**). This technique depends on many molecular properties to assess the structural similarity. These properties include the partition coefficient (ALog p) [49], molecular weight (M. Wt) [50], H-bond donors (HBA) [51], H-bond acceptors (HBD) [52], rotatable bond number [53], number of rings along with aromatic rings and minimum distance [54], as well as the molecular fractional polar surface area (MFPSA) [55]. Table 4 showed the different values for each tested compound, while Figure 15 showed the degree of similarity.


**Table 4.** Molecular properties of the tested FDA-approved drug and the synthesized compound **7**.

**Figure 15.** Molecular similarity study between the synthesized compound (green ball) and the FDAapproved 1*H*-inole derivatives (sunitinib, vorolanib, nintedanib, and toceranib). The red ball refers to toceranib (the most similar compound). The blue balls refer to sunitinib, vorolanib, and nintedanib (the less similar drugs).

The results revealed that toceranib **V** has the highest degree of similarity with the synthesized compound **7**.
