Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor

Chean Hui Ng, Kamal Rullah, Mohd Fadhlizil Fasihi Mohd. Aluwi, Faridah Abas, Kok Wai Lam, Intan Safinar Ismail, Radhakrishnan Narayanaswamy, Fadzureena Jamaludin, Khozirah Shaari

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11645-11659
Number of pages15
JournalMolecules
Volume19
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Lipoxygenase Inhibitors
Arachidonate 15-Lipoxygenase
inhibitors
Lipoxygenase
analogs
Soybeans
soybeans
Bearings (structural)
synthesis
Rutaceae
Acylation
Alkylation
Linoleic Acid
Structure-Activity Relationship
Medicinal Plants
Biological Products
Unsaturated Fatty Acids
acylation
Hydrogen Peroxide
Inhibitory Concentration 50

Keywords

  • Analogs
  • Friedel-Craft acylation
  • Friedel-Craft alkylation
  • Lipoxygenase
  • Molecular docking

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor. / Ng, Chean Hui; Rullah, Kamal; Mohd. Aluwi, Mohd Fadhlizil Fasihi; Abas, Faridah; Lam, Kok Wai; Ismail, Intan Safinar; Narayanaswamy, Radhakrishnan; Jamaludin, Fadzureena; Shaari, Khozirah.

In: Molecules, Vol. 19, No. 8, 2014, p. 11645-11659.

Research output: Contribution to journalArticle

Ng, CH, Rullah, K, Mohd. Aluwi, MFF, Abas, F, Lam, KW, Ismail, IS, Narayanaswamy, R, Jamaludin, F & Shaari, K 2014, 'Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor', Molecules, vol. 19, no. 8, pp. 11645-11659. https://doi.org/10.3390/molecules190811645
Ng, Chean Hui ; Rullah, Kamal ; Mohd. Aluwi, Mohd Fadhlizil Fasihi ; Abas, Faridah ; Lam, Kok Wai ; Ismail, Intan Safinar ; Narayanaswamy, Radhakrishnan ; Jamaludin, Fadzureena ; Shaari, Khozirah. / Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor. In: Molecules. 2014 ; Vol. 19, No. 8. pp. 11645-11659.
@article{5b3a98aefa1045d397d33fafde68b95b,
title = "Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor",
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.",
keywords = "Analogs, Friedel-Craft acylation, Friedel-Craft alkylation, Lipoxygenase, Molecular docking",
author = "Ng, {Chean Hui} and Kamal Rullah and {Mohd. Aluwi}, {Mohd Fadhlizil Fasihi} and Faridah Abas and Lam, {Kok Wai} and Ismail, {Intan Safinar} and Radhakrishnan Narayanaswamy and Fadzureena Jamaludin and Khozirah Shaari",
year = "2014",
doi = "10.3390/molecules190811645",
language = "English",
volume = "19",
pages = "11645--11659",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "8",

}

TY - JOUR

T1 - Synthesis and docking studies of 2,4,6-trihydroxy-3-geranylacetophenone analogs as potential lipoxygenase inhibitor

AU - Ng, Chean Hui

AU - Rullah, Kamal

AU - Mohd. Aluwi, Mohd Fadhlizil Fasihi

AU - Abas, Faridah

AU - Lam, Kok Wai

AU - Ismail, Intan Safinar

AU - Narayanaswamy, Radhakrishnan

AU - Jamaludin, Fadzureena

AU - Shaari, Khozirah

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Analogs

KW - Friedel-Craft acylation

KW - Friedel-Craft alkylation

KW - Lipoxygenase

KW - Molecular docking

UR - http://www.scopus.com/inward/record.url?scp=84906663673&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906663673&partnerID=8YFLogxK

U2 - 10.3390/molecules190811645

DO - 10.3390/molecules190811645

M3 - Article

C2 - 25100256

AN - SCOPUS:84906663673

VL - 19

SP - 11645

EP - 11659

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 8

ER -