| Summary: | We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-<i>b</i>]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO<sub>2</sub>, -CF<sub>3</sub>, and -CH<sub>3</sub>) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds <b>1</b>–<b>18</b>, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds <b>6</b> and <b>16</b> decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC<sub>50</sub>) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with <b>FDI-6</b>, in contrast to compound <b>1</b>, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds <b>1</b>–<b>18</b> in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density.
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