Potholing of the hydrophobic heme oxygenase-1 western region for the search of potent and selective imidazole-based inhibitors.

Here we report the design, synthesis, and molecular modeling of new potent and selective imidazole-based HO-1 inhibitors in which the imidazole nucleus and the hydrophobic groups are linked by a phenylethanolic spacer. Most of the tested compounds showed a good inhibitor activity with IC50 values in the low micromolar range, with two of them (1b and 1j) exhibiting also high selectivity toward HO-2. These results were obtained by the idea of potholing the entire volume of the principal hydrophobic western region with an appropriate ligand volume. Molecular modeling studies showed that these molecules bind to the HO-1 in the consolidated fashion where the imidazolyl moiety coordinates the heme iron while the aromatic groups are stabilized by hydrophobic interaction in the western region of the binding pocket. Finally, the synthesized compounds were analyzed for in silico ADME-Tox properties to establish oral drug-like behavior and showed satisfactory results.