The novel tetrasubstituted pyrrole derivatives 8g, 8h, and 8i showed selective cytotoxicity against M14 melanoma cells at low micromolar concentration. Structure-activity relationships (SARs) indicated the presence of three aromatic substituents on the pyrrole core as necessary for biological activity. Computational studies strongly suggest that the peculiar 3D orientation of these substituents is able to reproduce the hydrophobic side chains in LxxLL-like protein recognition motifs. Biological results showed altered p53 expression and nuclear translocation in cells sensitive to the compounds, suggesting p53 involvement in their anticancer mechanism of action. Unfortunately, because of poor solubility of the active analogues, it was not possible to perform further investigation by NMR techniques. Pharmacophore models were generated and used to perform 3D searches in molecular databases. Results indicated that two compounds share the same pharmacological profile and the same pharmacophoric features with our new derivatives, and one of them inhibited MDM2-MDM4 heterodimer formation.