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Molecules 2018, 23(5), 1209; https://doi.org/10.3390/molecules23051209

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

1
Department of Molecular Medicine, College of Medicine and Medical Sciences, Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama 329, Bahrain
2
Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy
3
Department of Chemical Sciences, University of Catania, V.le A. Doria, 95125 Catania, Italy
4
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
*
Authors to whom correspondence should be addressed.
Received: 8 May 2018 / Revised: 13 May 2018 / Accepted: 15 May 2018 / Published: 18 May 2018
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: HO-1; HO-2; HO-1 inhibitors; imidazole; docking studies; in silico profiling; ADME-toxicity HO-1; HO-2; HO-1 inhibitors; imidazole; docking studies; in silico profiling; ADME-toxicity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Greish, K.F.; Salerno, L.; Al Zahrani, R.; Amata, E.; Modica, M.N.; Romeo, G.; Marrazzo, A.; Prezzavento, O.; Sorrenti, V.; Rescifina, A.; Floresta, G.; Intagliata, S.; Pittalà, V. Novel Structural Insight into Inhibitors of Heme Oxygenase-1 (HO-1) by New Imidazole-Based Compounds: Biochemical and In Vitro Anticancer Activity Evaluation. Molecules 2018, 23, 1209.

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