Abstract
In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound
as a lead compound, in which an imidazole moiety is linked to a hydrophobic group by means of an ethanolic spacer. The tested compounds showed a good inhibitor activity and possessed IC
values in the micromolar range. These results were obtained by targeting the hydrophobic western region. Molecular modeling studies confirmed a consolidated binding mode in which the nitrogen of the imidazolyl moiety coordinated the heme ferrous iron, meanwhile the hydrophobic groups were located in the western region of HO-1 binding pocket. Moreover, the new compounds were screened for in silico ADME-Tox properties to predict drug-like behavior with convincing results. Finally, the in vitro antitumor activity profile of compound
was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound's
water solubility. Finally, compound
was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.