*2.2. Chemistry*

To authenticate the design and the interesting results of the computational studies, the targeted lead compound was synthesized according to Scheme 1. The commercially available material (4-aminobenzoic acid **1**) was first refluxed with methanol and sulfuric acid in accordance with the reported procedure, to afford methyl 4-aminobenzoate **2**. Benzoylation of methyl 4-aminobenzoate **2** was achieved in an ice bath via dropwise addition of benzoyl chloride **3** in DCM in the presence of TEA, to afford compound **4**. Refluxing compound **4** with hydrazine hydrate in ethanol afforded the corresponding acid hydrazide derivative **5**. A mixture of the acid hydrazide derivative **5** and 5-methoxy-1*H*indole-3-carbaldehyde **6** was refluxed in absolute ethanol and a few drops of glacial acetic acid, to afford the final target compound **7**.

The structure of compound **7** (Figure 17) was validated using spectral analysis. The IR spectrum showed absorption bands at 3287 cm<sup>−</sup>1, and 1645 cm<sup>−</sup><sup>1</sup> attributed to NH and the amidic carbonyl group, respectively. Moreover, 1H NMR spectra showed singlet signals around *δ* 11.48 and 10.53 ppm, corresponding to the indole NH and the two amidic NH protons. In addition, an up-field sharp singlet signal corresponding to OCH3 protons appeared at *δ* 3.82 ppm. The three protons (6, 7, and 9) of the phenyl ring of the *1H*-indol moiety resonated at *δ* 7.36 (d, *J* = 8.8 Hz), 6.88 (dd, *J* = 8.8, 2.4 Hz), and 7.79 (d, *J* = 2.4 Hz), respectively. At the same time, proton 2 was presented as a sharp singlet, peaking at *δ* 8.01. The characteristic proton, 10, resonated clearly as a sharp singlet signal at *δ* 8.62. Regarding the di para-substituted protons, protons (19, 21) and (18, 22) resonated at *δ* 7.58 (d, *J* = 8.2 Hz) and 7.99 (d, *J* = 8.2 Hz), respectively. Finally, the aromatic protons of

the benzamide moiety resonated at the overlapped areas of 7.68 and 7.96. Matching such findings, the 13C NMR spectra showed characteristic peaks corresponding to the two C=O and OCH3 groups around *δ* 166.34, 162.36, and 55.80 ppm, respectively. The carbons (2, 3, 4, 5, 6, 7, 8, and 9) of the phenyl ring of the *1H*-indol moiety resonated at *δ* (128.3, 112.8, 125.4, 130.4, 112.7, 111.9, 154.8, and 104.6, respectively). The characteristic carbon, 10, resonated at *δ* 154.2. The di para-substituted carbons (19, 21) and (18, 22) resonated at *δ* 119.9 and 128.2, respectively. The aromatic carbons (26, 27, 28, 29, 30, and 31) of the benzamide moiety resonated at *δ* (135.1, 128.2, 128.9, 132.5, 128.9, and 128.2, respectively).

**Scheme 1.** Synthetic pathway of target compound **7**.

**Figure 17.** Chemical structure of compound **7**.
