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Article

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

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Laboratory of Natural Products, Institute of Bioscience, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia
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School of Pharmacy, Management and Science University (MSU), University Drive, Off Persiaran Olahraga, Seksyen 13, Shah Alam 40100, Selangor, Malaysia
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Faculty of Pharmacy, Universiti Kebangsaan Malaysia (UKM), Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia
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Nanotechnology and Catalysis Research Centre (NANOCAT), Institute of Postgraduates Studies, University of Malaya (UM), Kuala Lumpur 50603, Malaysia
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Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia (UPM), Selangor Darul Ehsan, Serdang 43400, Selangor, Malaysia
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Forest Research Institute (FRIM), Selangor Darul Ehsan, Kepong 52109, Malaysia
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(10), 2509; https://doi.org/10.3390/molecules23102509
Received: 29 August 2018 / Revised: 18 September 2018 / Accepted: 25 September 2018 / Published: 30 September 2018
(This article belongs to the Section Medicinal 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 4ag (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 (3ag) showed no hepatotoxicity effect and were biodegradable, which indicated that they could be potentially safe drugs for treating inflammation. View Full-Text
Keywords: Analogues; lipoxygenase; in-silico; ADMET; TOPKAT Analogues; lipoxygenase; in-silico; ADMET; TOPKAT
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MDPI and ACS Style

Ng, C.H.; Rullah, K.; Abas, F.; Lam, K.W.; Ismail, I.S.; Jamaludin, F.; Shaari, K. 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 2018, 23, 2509. https://doi.org/10.3390/molecules23102509

AMA Style

Ng CH, Rullah K, Abas F, Lam KW, Ismail IS, Jamaludin F, Shaari K. 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. 2018; 23(10):2509. https://doi.org/10.3390/molecules23102509

Chicago/Turabian Style

Ng, Chean H., Kamal Rullah, Faridah Abas, Kok W. Lam, Intan S. Ismail, Fadzureena Jamaludin, and Khozirah Shaari. 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, no. 10: 2509. https://doi.org/10.3390/molecules23102509

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