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 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

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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 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

Item Type:	Article (Journal)
Additional Information:	9020/74949
Uncontrolled Keywords:	Keywords: Analogues; lipoxygenase; in-silico; ADMET; TOPKAT
Subjects:	R Medicine > RS Pharmacy and materia medica > RS403 Materia Medica-Pharmaceutical Chemistry
Kulliyyahs/Centres/Divisions/Institutes (Can select more than one option. Press CONTROL button):	Kulliyyah of Pharmacy > Department of Pharmaceutical Chemistry Kulliyyah of Pharmacy
Depositing User:	Dr Kamal Rullah
Date Deposited:	07 Nov 2019 16:09
Last Modified:	07 Nov 2019 16:09
URI:	http://irep.iium.edu.my/id/eprint/74949

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