Synthesis and Study of 2‑(Pyrrolesulfonylmethyl)‑<i>N</i>‑arylimines: A New Class of Inhibitors for Human Glutathione Transferase A1‑1

Overexpression of human GSTA1-1 in tumor cells is part of MDR mechanisms. We report on the synthesis of 11 pyrrole derivatives as hGSTA1-1 inhibitors starting from 1-methyl-2-[(2-nitrobenzylsulfanyl]-1<i>H</i>-pyrrole. Molecular modeling revealed two locations in the enzyme H binding site: the catalytic primary one accommodating shorter and longer derivatives and the secondary one, where shorter derivatives can occupy. Derivative <b>9</b>, displaying the highest inhibition and bearing a <i>p</i>-nitroarylimino moiety, and derivative <b>4</b>, lacking this moiety, were studied kinetically. Derivative <b>9</b> binds (<i>K</i>_i(<b>9</b>) = 71 ± 4 μM) at the primary site competitively vs CDNB. Derivative <b>4</b> binds (<i>K</i>_i(<b>4</b>) = 135 ± 27 μM) at the primary and secondary sites, allowing the binding of a second molecule (<b>4</b> or CDNB) leading to formation of unreactive and reactive complexes, respectively. The arylmethylsulfonylpyrrole core structure is a new pharmacophore for hGSTA1-1, whereas its derivative <b>9</b> may serve as a lead structure