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Molecules 2014, 19(8), 11645-11659; doi:10.3390/molecules190811645

Synthesis and Docking Studies of 2,4,6-Trihydroxy-3-Geranylacetophenone Analogs as Potential Lipoxygenase Inhibitor

1
Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia
2
Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia
3
Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 Serdang, Malaysia
4
Forest Research Institute (FRIM), Selangor Darul Ehsan, 52109 Kepong, Malaysia
*
Author to whom correspondence should be addressed.
Received: 1 July 2014 / Revised: 26 July 2014 / Accepted: 29 July 2014 / Published: 5 August 2014
(This article belongs to the Section Medicinal Chemistry)
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Abstract

The natural product molecule 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) isolated from the medicinal plant Melicope ptelefolia was shown to exhibit potent lipoxygenase (LOX) inhibitory activity. It is known that LOX plays an important role in inflammatory response as it catalyzes the oxidation of unsaturated fatty acids, such as linoleic acid to form hydroperoxides. The search for selective LOX inhibitors may provide new therapeutic approach for inflammatory diseases. Herein, we report the synthesis of tHGA analogs using simple Friedel-Craft acylation and alkylation reactions with the aim of obtaining a better insight into the structure-activity relationships of the compounds. All the synthesized analogs showed potent soybean 15-LOX inhibitory activity in a dose-dependent manner (IC50 = 10.31–27.61 μM) where compound 3e was two-fold more active than tHGA. Molecular docking was then applied to reveal the important binding interactions of compound 3e in soybean 15-LOX binding site. The findings suggest that the presence of longer acyl bearing aliphatic chain (5Cs) and aromatic groups could significantly affect the enzymatic activity. View Full-Text
Keywords: lipoxygenase; analogs; Friedel-Craft acylation; Friedel-Craft alkylation; molecular docking lipoxygenase; analogs; Friedel-Craft acylation; Friedel-Craft alkylation; molecular docking
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Ng, C.H.; Rullah, K.; Aluwi, M.F.F.M.; Abas, F.; Lam, K.W.; Ismail, I.S.; Narayanaswamy, R.; Jamaludin, F.; Shaari, K. Synthesis and Docking Studies of 2,4,6-Trihydroxy-3-Geranylacetophenone Analogs as Potential Lipoxygenase Inhibitor. Molecules 2014, 19, 11645-11659.

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