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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

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 acti...

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التفاصيل البيبلوغرافية
المؤلفون الرئيسيون: Ng, Chean Hui, Rullah, Kamal, Abas, Faridah, Lam, Kok Wai, Ismail, Intan Safinar, Jamaludin, Fadzureena, Shaari, Khozirah
التنسيق: مقال
منشور في: MDPI 2018
الموضوعات:
Q Science (General)
R Medicine
الوصول للمادة أونلاين:http://eprints.um.edu.my/21149/
https://doi.org/10.3390/molecules23102509
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id my.um.eprints.21149
record_format eprints
spelling my.um.eprints.211492019-05-07T07:43:17Z http://eprints.um.edu.my/21149/ 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 Q Science (General) R Medicine 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. MDPI 2018 Article PeerReviewed Ng, Chean Hui and Rullah, Kamal and Abas, Faridah and Lam, Kok Wai and Ismail, Intan Safinar and Jamaludin, Fadzureena and Shaari, Khozirah (2018) 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. Molecules, 23 (10). p. 2509. ISSN 1420-3049 https://doi.org/10.3390/molecules23102509 doi:10.3390/molecules23102509
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic Q Science (General)
R Medicine
spellingShingle Q Science (General)
R Medicine
Ng, Chean Hui
Rullah, Kamal
Abas, Faridah
Lam, Kok Wai
Ismail, Intan Safinar
Jamaludin, Fadzureena
Shaari, Khozirah
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
description 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.
format Article
author Ng, Chean Hui
Rullah, Kamal
Abas, Faridah
Lam, Kok Wai
Ismail, Intan Safinar
Jamaludin, Fadzureena
Shaari, Khozirah
author_facet Ng, Chean Hui
Rullah, Kamal
Abas, Faridah
Lam, Kok Wai
Ismail, Intan Safinar
Jamaludin, Fadzureena
Shaari, Khozirah
author_sort Ng, Chean Hui
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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher MDPI
publishDate 2018
url http://eprints.um.edu.my/21149/
https://doi.org/10.3390/molecules23102509
_version_ 1643691480125014016
score 13.252575

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