Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation.
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| Abstract |
In this paper, the design, synthesis, and molecular modeling of a new azole-based HO-1 inhibitors was reported, using compound 1 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 1 was investigated in different cancer cell lines and nanomicellar formulation was synthesized with the aim of improving compound's 1 water solubility. Finally, compound 1 was tested in melanoma cells in combination with doxorubicin showing interesting synergic activity.
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| Authors | Khaled F Greish, Loredana Salerno, Reem Al Zahrani, Emanuele Amata, Maria N Modica, Giuseppe Romeo, Agostino Marrazzo, Orazio Prezzavento, Valeria Sorrenti, Antonio Rescifina, Giuseppe Floresta, Sebastiano Intagliata, Valeria Pittalà |
| Journal | Molecules (Basel, Switzerland) (Molecules) Vol. 23 Issue 5 (May 18 2018) ISSN: 1420-3049 [Electronic] Switzerland |
| PMID | 29783634 (Publication Type: Journal Article) |
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