Results obtained from the modified compounds in series 4 indicated that the length of the substituted alkyl chain (R1) and type of substituted ring (R2) on the amino group at the C-2 position of the 1,4-naphthoquinone core affected the aromatase inhibitory activity of the compounds via the alterations of mass (Mor04m and H8m), electronegativity (Mor08e) and van der Waals volume (G1v). Substitution with the phenyl group (R2) of compounds 4a (R1 = C2H5) and 4b (R1 = C3H7) and with the 1-adamantyl group (R2) of compounds 4e (R1 = CH3) and 4f (R1 = C2H5) on the amino moiety led to highly potent compounds, whereas the compounds substituted with a cyclohexyl ring (R2), i.e., 4c (R1 = CH3) and 4d (R1 = C2H5), exhibited less potent activity. Apparently, substitution with a 2C (C2H5) alkyl chain (R1) in combination with a phenyl ring (R2) yielded a tertiary amine (4a), which was considered to be the most appropriate modification of 1,4-naphthoquinones with 2-substituted amino moieties. Among the modified compounds in series 4, compound 4a showed the lowest H8m value (0.002) but a relatively high G1v value (0.162).