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

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2018 May 23

PMID 29783634

Citations 25

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 Pittala

Affiliations

Soon will be listed here.

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.

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