Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation

Abstract

In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound <b>1</b> 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 IC₅₀ 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 <b>1</b> was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound's <b>1</b> water solubility. Finally, compound <b>1</b> was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.