The predictions showed that structural modifications can either improve or deteriorate the aromatase inhibitory activity of the compounds. 2,3-Disubstitution of the 1,4-naphthoquinone ring with halogen atoms (i.e., Br, I and F) was found to be the most effective strategy, as indicated by the highly potent activity of all modified compounds in series 1 (Table S4). Importantly, compound 1b exhibited the most potent activity among the tested and modified compounds, affording pIC50 values 11.90-fold and 1.03-fold greater than those of the parent compound 1 (experimental pIC50 0.301, Table S2) and the reference drug letrozole (experimental pIC50 3.482, Table S4), respectively. Greatly improved activity was also observed in other compounds in the same series, such as compound 1c (predicted pIC50 0.614, Table S4). This compound was ranked as the second most potent aromatase inhibitor, in which the activity was improved 2.04-fold compared to that of the parent compound 1. Likewise, compound 1a (predicted pIC50 0.550, Table S4) was the third most potent compound, with a 1.83-fold improvement in activity compared to that of parent compound 1. The effects of structural modifications were elucidated by analyzing the relationship between descriptor values and activity, as summarized in Supplementary Table S5. It could be deduced that the markedly improved activities of the modified compounds in series 1 may be governed by the substituted halogen atoms, which reduce the mass-weighted descriptor (Mor04m) values of the compounds. In particular, the lowest Mor04m value (-5.734) was observed for the most potent compound 1b, whereas the parent compound 1 exhibited the highest Mor04m value (1.226), followed by compounds 1a (0.479) and 1c (0.465). It should be noted that the modified compounds (1a, 1b, 1c) and the parent compound 1 showed the same values for the descriptors H8m, SIC2, and G1v (i.e., 0, 0.707 and 0.193, respectively). However, these compounds showed different Mor08e values: 1b = -0.583, 1a = -0.644, 1c = -0.757 and 1 = -0.928 (Table S1).