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Molecules 2017, 22(12), 2142; doi:10.3390/molecules22122142

Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

1
School of Pharmaceutical Science, Shanxi Medical University, 56 Xinjian South Road, Taiyuan 030001, China
2
Shanxi Key laboratory of Chronic Inflammatory Targeted Drugs, School of Chinese Materia Medica, Shanxi University of Traditional Chinese Medicine, 121 University Street, Jinzhong 030619, China
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 15 November 2017 / Revised: 29 November 2017 / Accepted: 2 December 2017 / Published: 4 December 2017
(This article belongs to the Section Medicinal Chemistry)
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Abstract

We previously reported 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9–6.3 μM, which were stronger than that of quercetin (EC50: 18.0 μM), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 μM equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury. View Full-Text
Keywords: heterocycle; bromophenol; synthesis; molecular docking; kelch-like ECH-associated protein 1 protein heterocycle; bromophenol; synthesis; molecular docking; kelch-like ECH-associated protein 1 protein
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MDPI and ACS Style

Feng, X.E.; Wang, Q.J.; Gao, J.; Ban, S.R.; Li, Q.S. Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking. Molecules 2017, 22, 2142.

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