*Rationale*

Figure 1 demonstrates some reported and FDA-approved VEGFR-2 inhibitors such as sorafenib **I** [34], sunitinib **II** [35], vorolanib **III** [36], nintedanib **IV** [37], and toceranib **V** [38]. These drugs have four key pharmacophoric features that must exist in any inhibitor to fit with the VEGFR-2 active site. The four key features are aromatic ring, spacer moiety, pharmacophore moiety (comprising hydrogen bond donor and hydrogen bond acceptor atoms), and hydrophobic group [20,39,40].

Regarding sunitinib **II**, vorolanib **III**, nintedanib **IV**, and toceranib **V,** these drugs possess 1*H*-indole derivatives as hetero aromatic structures that can occupy the hinge region of the VEGFR-2 active site. In all compounds, it was noticed that the 1*H*-indole derivatives share three characteristics. (i) The NH group at the 1-position was kept free without any substitution. (ii) Except nintedanib **IV**, the 5-position was substituted with the hydrophobic (fluoro) group. (iii) The 1*H*-indole moiety was attached to the rest of the structures at the 3-position. Moreover, sunitinib **II**, vorolanib **III**, nintedanib **IV**, and toceranib **V** have an amide moiety as a pharmacophore that binds the DFG motif region and forms essential hydrogen bonds with Asp1044 and Glu833.

Taking these characteristics into consideration, we designed a modified analog that kept the main characteristics of the lead compounds (**II**–**V**). As appeared in Figure 2, the designed molecule has a 1*H*-indole moiety as a hetero aromatic structure that can occupy the hinge region of the VEGFR-2 active site. The 1*H*-indole moiety has a free NH group with a substitution at the 5-position with a hydrophobic methoxy group. In addition, the 1*H*-indole moiety was attached to the rest of the structures at the 3-position as in the lead compounds. Furthermore, the designed molecule has an amide moiety as a pharmacophore that binds the DFG motif region at the VEGFR-2 active site. The linker structure of the designed compound consisted of an *N* -methylene benzohydrazide moiety that can form hydrophobic and hydrophilic interactions at the gatekeeper region. Finally, a plain phenyl ring was utilized as a hydrophobic tail in the designed molecule to form a hydrophobic interaction at the allosteric binding pocket.

**Figure 1.** Sorafenib and some FDA-approved 1*H*-indole derivatives working as VEGFR-2 inhibitors show the essential pharmacophoric features.

**Figure 2.** The design rationale of the targeted compound.
