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

Molecules

Chean Hui Ng¹  Kamal Rullah²  Mohd Fadhlizil Fasihi Mohd Aluwi²  Faridah Abas¹  Kok Wai Lam²  Intan Safinar Ismail¹  Radhakrishnan Narayanaswamy¹  Fadzureena Jamaludin³ 

[1] Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, 43400 UPM Serdang, Malaysia; E-Mails:;Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia; E-Mails:;Forest Research Institute (FRIM), Selangor Darul Ehsan, 52109 Kepong, Malaysia; E-Mail:

关键词: lipoxygenase;    analogs;    Friedel-Craft acylation;    Friedel-Craft alkylation;    molecular docking;   

DOI  :  10.3390/molecules190811645

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.