Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (thga) as a potent lox inhibitor: Synthesis, structure-activity relationship (sar) study, and computational assignment

Chean Hui Ng, Kamal Rullah, Faridah Abas, Kok Wai Lam, Intan Safinar Ismail, Fadzureena Jamaludin, Khozirah Shaari

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a-g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a-g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

Original languageEnglish
Article number2509
JournalMolecules
Volume23
Issue number10
DOIs
Publication statusPublished - 30 Sep 2018

Fingerprint

Structure-Activity Relationship
inhibitors
Lipoxygenase
analogs
Inhibitory Concentration 50
optimization
synthesis
Toxicity
toxicity
Molecular Dynamics Simulation
Hydrophobic and Hydrophilic Interactions
Chain length
Metabolism
Computer Simulation
Molecular dynamics
excretion
metabolism
Inflammation
Technology
Kinetics

Keywords

  • ADMET
  • Analogues
  • In-silico
  • Lipoxygenase
  • TOPKAT

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (thga) as a potent lox inhibitor : Synthesis, structure-activity relationship (sar) study, and computational assignment. / Ng, Chean Hui; Rullah, Kamal; Abas, Faridah; Lam, Kok Wai; Ismail, Intan Safinar; Jamaludin, Fadzureena; Shaari, Khozirah.

In: Molecules, Vol. 23, No. 10, 2509, 30.09.2018.

Research output: Contribution to journalArticle

@article{cf48d14f9ea140f5a00ee40657d703b7,
title = "Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (thga) as a potent lox inhibitor: Synthesis, structure-activity relationship (sar) study, and computational assignment",
abstract = "A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a-g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a-g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.",
keywords = "ADMET, Analogues, In-silico, Lipoxygenase, TOPKAT",
author = "Ng, {Chean Hui} and Kamal Rullah and Faridah Abas and Lam, {Kok Wai} and Ismail, {Intan Safinar} and Fadzureena Jamaludin and Khozirah Shaari",
year = "2018",
month = "9",
day = "30",
doi = "10.3390/molecules23102509",
language = "English",
volume = "23",
journal = "Molecules",
issn = "1420-3049",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

TY - JOUR

T1 - Hits-to-lead optimization of the natural compound 2,4,6-trihydroxy-3-geranyl-acetophenone (thga) as a potent lox inhibitor

T2 - Synthesis, structure-activity relationship (sar) study, and computational assignment

AU - Ng, Chean Hui

AU - Rullah, Kamal

AU - Abas, Faridah

AU - Lam, Kok Wai

AU - Ismail, Intan Safinar

AU - Jamaludin, Fadzureena

AU - Shaari, Khozirah

PY - 2018/9/30

Y1 - 2018/9/30

N2 - A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a-g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a-g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

AB - A new series of 2,4,6-trihydroxy-3-geranyl-acetophenone (tHGA) analogues were synthesized and evaluated for their lipoxygenase (LOX) inhibitory activity. Prenylated analogues 4a-g (half maximal inhibitory concentration (IC50) values ranging from 35 μM to 95 μM) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μM) due to the reduction in hydrophobic interaction when the alkyl chain length was reduced. One geranylated analogue, 3d, with an IC50 value of 15.3 μM, exhibited better LOX inhibitory activity when compared to tHGA (3a), which was in agreement with our previous findings. Kinetics study showed that the most active analogue (3e) and tHGA (3a) acted as competitive inhibitors. The combination of in silico approaches of molecular docking and molecular dynamic simulation revealed that the lipophilic nature of these analogues further enhanced the LOX inhibitory activity. Based on absorption, distribution, metabolism, excretion, and toxicity (ADMET) and toxicity prediction by komputer assisted technology (TOPKAT) analyses, all geranylated analogues (3a-g) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation.

KW - ADMET

KW - Analogues

KW - In-silico

KW - Lipoxygenase

KW - TOPKAT

UR - http://www.scopus.com/inward/record.url?scp=85054065151&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054065151&partnerID=8YFLogxK

U2 - 10.3390/molecules23102509

DO - 10.3390/molecules23102509

M3 - Article

C2 - 30274341

AN - SCOPUS:85054065151

VL - 23

JO - Molecules

JF - Molecules

SN - 1420-3049

IS - 10

M1 - 2509

ER -