Lipoxygenase Inhibition Activity of Coumarin Derivatives-QSAR and Molecular Docking Study.

Melita Lončarić,Domagoj Šubarić,Valentina Pavić,Maja Molnar,Ivica Strelec,Vesna Rastija

doi:10.3390/ph13070154

Abstract

Lipoxygenases (LOXs) are a family of enzymes found in plants, mammals, and microorganisms. In animals and plants, the enzyme has the capability for the peroxidation of unsaturated fatty acids. Although LOXs participate in the plant defense system, the enzyme’s metabolites can have numerous negative effects on human health. Therefore, many types of research are searching for compounds that can inhibit LOXs. The best quantitative structure–activity relationship (QSAR) model was obtained using a Genetic Algorithm (GA). Molecular docking was performed with iGEMDOCK. The inhibition of lipoxygenase was in the range of 7.1 to 96.6%, and the inhibition of lipid peroxidation was 7.0–91.0%. Among the synthesized compounds, the strongest inhibitor of soybean LOX-3 (96.6%) was found to be 3-benzoyl-7-(benzyloxy)-2H-chromen-2-one. A lipid peroxidation inhibition of 91.0% was achieved with ethyl 7-methoxy-2-oxo-2H-chromene-3-carboxylate. The docking scores for the soybean LOX-3 and human 5-LOX also indicated that this compound has the best affinity for these LOX enzymes. The best multiple linear QSAR model contains the atom-centered fragment descriptors C-06, RDF035p, and HATS8p. QSAR and molecular docking studies elucidated the structural features important for the enhanced inhibitory activity of the most active compounds, such as the presence of the benzoyl ring at the 3-position of coumarin’s core. Compounds with benzoyl substituents are promising candidates as potent lipoxygenase inhibitors.

Highlights

Lipoxygenases (EC 1.13.11.12, linoleate: oxygen, oxidoreductases, LOXs) are non-heme, iron-containing enzymes that catalyze the deoxygenation of polyunsaturated fatty acids containing a 1-cis,4-cis-pentadiene structure, resulting in the formation of conjugated diene hydroperoxides [1,2]
Based on the published research and our interest in coumarin derivatives, in this paper, we present in vitro lipid peroxidation and the soybean lipoxygenase inhibitory activity of coumarins
Five series of coumarin derivatives were synthesized in the reaction of substituted salicylaldehydes and dimethyl malonate (Series 1—2, 12, 16, 20, 27, 30, 36), diethyl malonate (Series 2 —3, 17, 21, 24, 26, 28, 33, 37), ethyl benzoylacetate (Series 3—5, 7, 13, 23, 25, 35, 38, 39), ethyl cyanoacetate (Series 4—4, 6, 10, 18, 22, 29, 31, 34), and ethyl acetoacetate (Series 5—1, 9, 11, 14, 15, 19, 32)

Summary

Introduction

Lipoxygenases (EC 1.13.11.12, linoleate: oxygen, oxidoreductases, LOXs) are non-heme, iron-containing enzymes that catalyze the deoxygenation of polyunsaturated fatty acids containing a 1-cis,4-cis-pentadiene structure, resulting in the formation of conjugated diene hydroperoxides [1,2]. LOXs are very important enzymes in plants, because of many lipoxygenase pathway products such as jasmonates, leaf alcohols, and antimicrobial and antifungal compounds such as leaf aldehydes and divinyl ethers [6,7]. All these products play an important role in the plant’s interaction with pathogens, insects, or abiotic stress [8]. LOXs can cause food spoilage (off-flavors and off-odors) due to their reactions with unsaturated fatty acids [11]. Different organic compounds are reported as LOX inhibitors such as coumarins [12,13], rhodanines [14,15], thiazolidinediones [16], and quinazolinone-1,2,3-triazoles [17]

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Results

Conclusion