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 μ M to 95 μ M) did not exhibit better inhibitory ac...
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| Format: | Article |
| Language: | English |
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MDPI
2018
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| Online Access: | http://irep.iium.edu.my/74949/ http://irep.iium.edu.my/74949/1/Kamal%20Rullah%2020.pdf |
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| 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 |
| building | IIUM Repository |
| collection | Online Access |
| 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 μ M to 95 μ M) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μ M) 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 μ M, 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 |
| first_indexed | 2025-11-14T17:34:31Z |
| format | Article |
| id | iium-74949 |
| institution | International Islamic University Malaysia |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-14T17:34:31Z |
| publishDate | 2018 |
| publisher | MDPI |
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| repository_type | Digital Repository |
| spelling | iium-749492019-11-07T08:09:54Z http://irep.iium.edu.my/74949/ 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 RS403 Materia Medica-Pharmaceutical Chemistry 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 μ M to 95 μ M) did not exhibit better inhibitory activity than tHGA (3a) (IC50 value: 23.6 μ M) 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 μ M, 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 2018-09-30 Article PeerReviewed application/pdf en http://irep.iium.edu.my/74949/1/Kamal%20Rullah%2020.pdf 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). pp. 1-19. ISSN 1420-3049 https://www.mdpi.com/1420-3049/23/10/2509/htm 10.3390/molecules23102509 |
| spellingShingle | RS403 Materia Medica-Pharmaceutical Chemistry 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 |
| 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_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_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_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 |
| topic | RS403 Materia Medica-Pharmaceutical Chemistry |
| url | http://irep.iium.edu.my/74949/ http://irep.iium.edu.my/74949/ http://irep.iium.edu.my/74949/ http://irep.iium.edu.my/74949/1/Kamal%20Rullah%2020.pdf |