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.
Highlights
Lipoxygenases (LOXs) are a family of nonheme iron-containing enzymes that are involved in the oxygenation of polyunsaturated fatty acids (PUFAs) containing cis–cis 1–4 pentadiene structures to give hydroperoxy derivatives
We reported the synthesis of the acylphloroglucinols (2b–c, 2e–g) and geranylated analogues
Our results show that both tHGA (3a) and compound 3e inhibited catalytic activity of the soybean 15-LOX as a function of increasing concentration of the compound
Summary
Lipoxygenases (LOXs) are a family of nonheme iron-containing enzymes that are involved in the oxygenation of polyunsaturated fatty acids (PUFAs) containing cis–cis 1–4 pentadiene structures to give hydroperoxy derivatives. LOXs can be found in plant and animal tissues [1]. They can be classified as 5-, 8-, 9-, 11-, 12-, and 15-LOXs based on their positional specificity of arachidonic acid oxidation [2]. LOXs targets for for rational drugdrug design since they involved in a variety disorders, LOXsare arepotential potential targets rational design sinceare they are involved in of a variety of such as bronchial asthma, inflammation, cancer, and autoimmune diseases [3]. 5-LOX disorders, such as bronchial asthma, inflammation, cancer, and autoimmune diseases [3]. The human pathway is the source potentofproinflammatory mediators [4].
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